Compound having kdm5 inhibitory activity and pharmaceutical use thereof

ABSTRACT

Disclosed are compounds of following formula (I):in which all symbols have the same meanings as the definitions described in the specification; or a salt thereof. The compounds or a salt thereof are useful as a prophylactic and/or therapeutic agent for cancer, Huntington&#39;s disease, Alzheimer&#39;s disease and the like.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a bypass continuation of and claims the benefits ofPCT/CN21/091843 filed May 6, 2021, which claims the benefit of ChinesePatent Application No. PCT/CN2020/088925, filed on May 7, 2020 in theChinese Intellectual Property Office, the disclosures of which areincorporated herein by reference in their entireties.

TECHNICAL FIELD

The present invention relates to a compound represented by the generalformula (I) described hereinbelow having KDM5 inhibitory activity, or asalt thereof, and pharmaceutical use thereof.

BACKGROUND ART

Eukaryotic DNA exists in the nucleus as a chromatin structure that is acomplex with histone proteins. Histone proteins are subject tomodifications such as methylation, acetylation and phosphorylationthrough various enzymes, and changes in such modifications are known toinduce chromatin remodelling and transcriptional alterations. Epigeneticmodifications including histone methylation reversely regulate geneexpression without altering the nucleotide sequence and play animportant role in physiological processes.

KDM5 proteins are members of JARID histone demethylase protein family,which demethylates tri-methylation of the fourth lysine residue ofhistone H3 protein (H3K4me3). In mammalian species including humans,there are four subfamilies: KDM5A, KDM5B, KDM5C, and KDM5D, which havefive conserved domains, namely JmjN, ARID, JmjC, PHDs, and C5HC2 zincfinger. The KDM5 family is widely distributed in blood cells and variousorgans, in vivo, and particularly, is known to be highly expressed incancer tissues. Epigenetic aberrations in cancer cells are known to beinvolved in the cell proliferation and metastasis, and KDM5 inhibitorshave been reported to have efficacy against cancer cells. Theinvolvement of epigenetic abnormalities, including histonemodifications, has also been reported in other pathologies, such asneuropsychiatric disorders and metabolic diseases. Therefore, compoundswith KDM5 inhibitory activity may improve the epigenetic abnormalitiesand be useful for the prevention and treatment of these diseases.

In related art of the present invention, WO2016057924 reports thatcompounds of formula (A) are useful as inhibitors of one or more histonedemethylases such as KDM5.

or a salt thereof, wherein:A^(A) is selected from the group consisting of:

R^(1A) is alkyl, cyclic group, or the like;R^(2A) is optionally substituted cyclic group, —OR^(aA),—C(O)N(R^(aA))₂, or NR^(aA)R^(bA);R^(aA) and R^(bA) are each independently selected from H, optionallysubstituted alkyl group, optionally substituted cyclic group, etc.;R^(3A) is H or alkyl;R^(4A) is H, alkyl, or cyclic group; andR^(5A) is H, halo, or alkyl, andR^(6A) is H, alkyl, or cyclic group;or R^(5A) and R^(6A) taken together to form cyclic group (where thedefinitions of the groups are excerpted).

In addition, WO2000039089 reports that compounds represented by thefollowing formula (B) are useful as opiate receptors ligands.

wherein the Ar^(B) ring represents an optionally benzo-fused phenyl or5- or 6-membered heteroaryl ring;R^(1B) is selected from various substituents;R^(2B) is H or halogen;R^(3B) is H, halogen, alkyl group, cyclic group, or the like,R^(4B) is optionally substituted alkyl, alkenyl or alkynyl,R^(5B) and R^(8B) are each independently H or C₁₋₆ alkyl,R^(6B), R^(7B), R^(9B) and R^(10B) when taken separately are H,X is halogen, alkyl, alkoxy, or the like (where the definitions of thegroups are excerpted) or a pharmaceutically or veterinarily acceptablederivative or prodrug thereof.

In addition, WO2021010492 reports that compounds of formula (C) areuseful as KDM5 inhibitor.

wherein ring^(C) is 3- to 10-membered mono or bicyclic hetero ringcontaining 1 to 4 nitrogen atoms, one oxygen atom and/or one sulfuratom, which may be substituted with 1 to 3 substituents;A^(C) is R_(1-1C)-L_(1C)-, or the like;B^(C) is R^(2-1C)-L^(2C)-, or the like;R^(1-1C) is a C3-8 cycloalkyl which may be substituted with 1 to 4substituents, or the like;L^(1C) is a bond, or carbonyl(—C(═O)—);L^(2C) is a bond, carbonyl(—C(═O)—), or the like;R^(2-1C) is 5- or 6-membered monocyclic heterocycle which may besubstituted with 1 to 4 substituents, or the like;R^(3C) is a hydrogen atom, or the like;r^(C) represents an integer of 0 to 1;or a salt thereof.

CITATION LIST Patent Literature

-   [PTL 1] WO 2016/057924-   [PTL 2] WO 2000/039089-   [PTL 3] WO 2021/010492

SUMMARY OF INVENTION Technical Problem

For example, a compound having KDM5 inhibitory activity for thetreatment or prevention of diseases such as cancer, Huntington'sdisease, Alzheimer's disease and the like has been desired.

Solution to Problem

The inventors of the present invention have carried out extensivestudies in order to achieve the above problem, and as a result, foundthat the compound represented by the general formula (I) describedhereinafter, or a salt thereof can achieve the above object. Theinventors have carried out further researches and completed the presentinvention.

Thus the present invention relates to:

[1] A compound represented by the general formula (I):

wherein R¹ represents Cyc1, —CO-Cyc2 or —CONR¹⁰R¹¹;Cyc1 represents a 5 to 9 membered aromatic hetero ring or 5 memberednon-aromatic hetero ring, each of which may be substituted with 1 to 5R¹²;R¹² represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl,(4) C1-4 alkoxy, (5) phenyl which may be substituted with 1 to 3 R¹⁷,(6) C1-4 alkyl which is substituted with phenyl, (7) dimethylamino, (8)pyridyl or (9) 1-(cyclopropylmethyl)pyrazol-3-yl;a plurality of R¹² may be the same or different;two R¹² together with an atom to which these R¹² are attached may form aC3-5 cycloalkane,wherein the carbon atom of C3-5 cycloalkane may be replaced with heteroatom selected from 1 to 2 N, O and S;R¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen;a plurality of R¹⁷ may be the same or different;Cyc2 represents a C3-12 mono or bicyclic carbocycle or a 5- to9-membered mono or bicyclic heterocycle, each of which may besubstituted with 1 to 5 R¹³;R¹³ represents C1-4 alkyl, C1-4 alkoxy or halogen;a plurality of R¹³ may be the same or different;R¹⁰ represents

wherein R¹⁸ and R¹⁹ independently represents C1-4 alkyl;R¹⁸ and R¹⁹ together with a carbon atom to which R¹⁸ and R¹⁹ areattached may form a C3-5 cycloalkane;R²⁰ represents a hydrogen atom, C1-4 alkyl, C1-4 haloalkyl or nitrile;(in the group, the arrow indicates the binding to the nitrogen atom of—CONC);R¹¹ represents a hydrogen atom, C1-4 alkyl or 1 to 9 deuterated C1-4alkyl;R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ independently represent a hydrogen atom,C1-4 alkyl, halogen or C1-4 alkoxy;R⁹ represents imidazole which may be substituted with 1 to 3 R¹⁴ orpyrazole which may be substituted with 1 to 3 R¹⁵;R¹⁴ represents (1) C1-8 alkyl, (2) C3-7 cycloalkyl which may besubstituted with C1-4 alkyl, (3) C1-8 haloalkyl, (4) C1-8 alkyl which issubstituted with Cyc3 which may be substituted with 1 to 3 R¹⁶ or (5)C1-8 alkyl which is substituted with phenoxy;Cyc3 represents phenyl, C3-7 cycloalkyl, pyridyl, thiazolyl ortetrahydropyranyl;R¹⁶ represents C1-4 alkyl, halogen, C1-4 alkoxy or cyano;a plurality of R¹⁴ may be the same or different;a plurality of R¹⁶ may be the same or different;R¹⁵ represents (1) C1-8 alkyl, (2) C3-7 cycloalkyl which may besubstituted with C1-4 alkyl, (3) C1-8 haloalkyl, (4) C1-8 alkyl which issubstituted with Cyc4 which may be substituted with 1 to 3 R²¹ or (5)C1-8 alkyl which is substituted with phenoxy;Cyc4 represents phenyl, C3-7 cycloalkyl, pyridyl, thiazolyl ortetrahydropyranyl;R²¹ represents C1-4 alkyl, halogen, C1-4 alkoxy or cyano;a plurality of R⁵ may be the same or different;a plurality of R²¹ may be the same or different;each hydrogen atom may be a deuterium atom or a tritium atom;with the proviso that((1R,5S,6r)-6-(Cyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexan-3-yl)(5-isopropyl-1H-pyrazol-3-yl)methanone,(5-Isopropyl-1H-pyrazol-3-yl)-[(1R,5S)-6-[(2R)-2-methylpyrrolidine-1-carbonyl]-3-azabicyclo[3.1.0]hexan-3-yl]methanone,(5-Isopropyl-1H-pyrazol-3-yl)-[(1S,5R)-6-[(2S)-2-methylpyrrolidine-1-carbonyl]-3-azabicyclo[3.1.0]hexan-3-yl]methanone,[(1S,5R)-6-(2,2-Dimethylpyrrolidine-1-carbonyl)-3-azabicyclo[3.1.0]hexan-3-yl]-(5-isopropyl-1H-pyrazol-3-yl)methanoneand(5-Isopropyl-1H-pyrazol-3-yl)-[(1S,5R)-6-(5-methyl-4-phenyl-isoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl]methanoneare excluded;or a salt thereof;[2] The compound according to the preceding item [1], wherein R¹represents Cyc1, and the Cyc1 represents 5 membered non-aromatic heteroring which may be substituted with 1 to 5 R¹², or a salt thereof;[3] The compound according to the preceding item [2], wherein 5 memberednon-aromatic hetero ring represents 4,5-dihydroisoxazole or4,5-dihydro-1,2,4-oxadiazole, or a salt thereof;[3-1] The compound according to the preceding item [3], wherein thecompound represented by the general formula (I) is represented by thegeneral formula (I-01)

wherein R¹²⁻¹ and R¹²⁻² independently represent C1-4 alkyl;R¹²⁻¹ and R¹²⁻² together with an atom to which the R¹²⁻¹ and R¹²⁻² arebound may form C3-5 cycloalkane;other symbols represent the same meaning as described in the precedingitem [1];or a salt thereof;[4] The compound according to any one of the preceding item [1] to [3]and [3-1], wherein R⁹ represents imidazole which may be substituted with1 to 3 R¹⁴, or a salt thereof;[5] The compound according to any one of the preceding item [1] to [4]and [3-1], wherein the compound represented by the general formula (I)is represented by the general formula (I-1)

wherein R¹²⁻¹ and R¹²⁻² independently represent C1-4 alkyl;R¹²⁻¹ and R¹²⁻² together with an atom to which the R¹²⁻¹ and R¹²⁻² arebound may form C3-5 cycloalkane;R¹⁴⁻¹ represents C1-4 alkyl or C3-5 cycloalkyl which may be substitutedwith C1-4 alkyl;other symbols represent the same meaning as described in [1];or a salt thereof;[6] The compound according to any one of the preceding item [1] to [5]and [3-1], wherein the compound is:

-   (1)    [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone;-   (2)    [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone;-   (3)    (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]methanone;-   (4)    (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone;-   (5)    {1-[(2S)-butan-2-yl]-1H-imidazol-4-yl}[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone;-   (6)    [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone;-   (7)    (1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone;-   (8)    (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone    or-   (9)    [1-(1-methylcyclopropyl)-1H-imidazol-4-yl][(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone;    or a salt thereof;    [7] The compound according to any one of the preceding item [1] to    [3] and [3-1], wherein R⁹ represents pyrazole which may be    substituted with 1 to 3 R¹⁵ or a salt thereof;    [8] The compound according to any one of the preceding item [1] to    [3], [3-1] and [7], wherein the compound represented by the general    formula (I) is represented by the general formula (I-2)

wherein all symbols represent the same meaning as described in thepreceding item [1] or [5]; or a salt thereof;[9] The compound according to any one of the preceding item [1] to [3],[3-1], [7] and [8] wherein the compound is:

-   (1)    [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone;-   (2)    (5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone;-   (3)    [5-(1-cyclopropylethyl)-1H-pyrazol-3-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone;-   (4)    [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone    or-   (5)    (5-cyclopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone    or a salt thereof;    [10] The compound according to the preceding item [1], wherein R¹    represents —CONR¹⁰R¹¹,    or a salt thereof;    [11] The compound according to the preceding item [1] or [10],    wherein R¹⁰ represents isopropyl, tert-butyl,    1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl,    1-(trifluoromethyl)cyclopropyl or 1-cyanocyclopropyl, or a salt    thereof;    [11-1] The compound according to the preceding item [11], wherein    the compound represented by the general formula (I) is represented    by the general formula (I-02)

wherein R¹⁰⁻¹ represents isopropyl, tert-butyl,1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl,1-(trifluoromethyl)cyclopropyl or 1-cyanocyclopropyl;other symbols represent the same meaning as described in the precedingitem [1]; or a salt thereof;[12] The compound according to the preceding item [10], [11] or [11-1],wherein R⁹ represents imidazole which may be substituted with 1 to 3R¹⁴, or a salt thereof;[13] The compound according to any one of the preceding item [1], [10]to [12] and [11-1], wherein the compound represented by the generalformula (I) is represented by the general formula (I-3)

wherein R¹⁰⁻¹ represents isopropyl, tert-butyl,1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl,1-(trifluoromethyl)cyclopropyl or 1-cyanocyclopropyl;other symbols represent the same meaning as described in the precedingitem [1] or [5]; or a salt thereof;[14] The compound according to any one of the preceding item [1], [10]to [13] and [11-1] wherein the compound is:

-   (1)    (1R,5S,6r)-N-tert-butyl-6-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide;-   (2)    (1R,5S,6r)-N-tert-butyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide;-   (3)    (1R,5S,6r)-N-(propan-2-yl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide    or-   (4)    (1R,5S,6r)-N-(1-cyanocyclopropyl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide    or a salt thereof;    [15] The compound according to the preceding item [10], [11] and    [11-1], wherein R⁹ represents pyrazole which may be substituted with    1 to 3 R¹⁵ or a salt thereof;    [16] The compound according to any one of the preceding item [1],    [10], [11], [11-1] and [15], wherein the compound represented by the    general formula (I) is represented by the general formula (I-4)

wherein all symbols represent the same meaning as described in thepreceding item [1] or [13];or a salt thereof;[17] The compound according to any one of the preceding item [1], [10],[11], [11-1], [15] and [16], wherein the compound is:

-   (1)    (1R,5S,6r)-N-(propan-2-yl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide;-   (2)    (1R,5S,6r)-N-tert-butyl-6-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide;-   (3)    (1R,5S,6r)-N-tert-butyl-N-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide    or-   (4)    (1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide,    or a salt thereof;    [18] A pharmaceutical composition comprising the compound    represented by the general formula (I) according to the preceding    item [1] or a salt thereof, and a pharmaceutically acceptable    carrier;    [19] The pharmaceutical composition according to the preceding item    [18], which is KDM5 inhibitor;    [20] The pharmaceutical composition according to the preceding item    [18] or [19], which is a prophylactic and/or therapeutic agent for    KDM5-related disease;    [21-1] The pharmaceutical composition according to the preceding    item [20], wherein the KDM5-related disease is hyperproliferative    disease, cancer, stroke, diabetes, hepatomegaly, cardiovascular    disease, multiple sclerosis, Huntington's disease, Alzheimer's    disease, cystic fibrosis, viral disease, autoimmune diseases,    atherosclerosis, restenosis, psoriasis, rheumatoid arthritis,    inflammatory bowel disease, asthma, allergic disorders,    inflammation, neurological disorders, a hormone-related disease,    conditions associated with organ transplantation, immunodeficiency    disorders, destructive bone disorders, proliferative disorders,    infectious diseases, conditions associated with cell death,    thrombin-induced platelet aggregation, liver disease, pathologic    immune conditions involving T cell activation, CNS disorders,    myeloproliferative disorder, Parkinson's disease, Lewy body disease,    frontotemporal lobar degeneration, mild cognitive impairment,    cognitive impairment, cerebrovascular disease, schizophrenia,    depression, anxiety disorder, bipolar disorder, autism spectrum    disorder, attention deficit/hyperactivity disorder, learning    disabilities, movement disorders, obsessive-compulsive disorder,    personality disorder, sleeping disorder, delirium, amyotrophic    lateral sclerosis, developmental disorders, intellectual disability,    post-traumatic stress disorder, or hepatitis;    [21-2] The pharmaceutical composition according to the preceding    item [20], wherein the KDM5-related disease is cancer, or Alzheimer    Disease;    [22] A prophylactic and/or therapeutic agent for KDM5-related    disease, comprising the compound represented by the general    formula (I) according to the preceding item [1] or a salt thereof as    an active component, wherein the prophylactic and/or therapeutic    agent is administered together with at least one drug selected from    the group consisting of donepezil hydrochloride, galantamine    hydrobromide, huperzine A, idebenone, levacecarnine hydrochloride,    memantine hydrochloride, memantine hydrochloride/donepezil    hydrochloride, proteolytic peptide fraction from porcine brain    protein, rivastigmine tartrate, tacrine hydrochloride and    aducanumab;    [23] A method for prophylaxis and/or therapy of KDM5-related    disease, comprising administering to a mammal (preferably, a patient    in need thereof) an effective amount of the compound represented by    the general formula (I) according to the preceding item [1] or a    salt thereof;    [24] The compound represented by the general formula (I) according    to the preceding item [1] or a salt thereof for use in prophylaxis    and/or therapy of KDM5-related disease; and    [25] Use of the compound represented by the general formula (I)    according to the preceding item [1] or a salt thereof in the    manufacture of a prophylactic and/or therapeutic agent for    KDM5-related disease.

Advantageous Effects of Invention

The compound represented by the general formula (I) or a salt thereof(hereinafter collectively referred to as the present compound) asdisclosed herein has KDM5 inhibitory activity. Therefore, the presentcompound can be used as a therapeutic and/or prophylactic agent fordiseases such as hyperproliferative disease, cancer, stroke, diabetes,hepatomegaly, cardiovascular disease, multiple sclerosis, Huntington'sdisease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmunediseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis,inflammatory bowel disease, asthma, allergic disorders, inflammation,neurological disorders, a hormone-related disease, conditions associatedwith organ transplantation, immunodeficiency disorders, destructive bonedisorders, proliferative disorders, infectious diseases, conditionsassociated with cell death, thrombin-induced platelet aggregation, liverdisease, pathologic immune conditions involving T cell activation, CNSdisorders, myeloproliferative disorder, Parkinson's disease, Lewy bodydisease, frontotemporal lobar degeneration, mild cognitive impairment,cognitive impairment, cerebrovascular disease, schizophrenia,depression, anxiety disorder, bipolar disorder, autism spectrumdisorder, attention deficit/hyperactivity disorder, learningdisabilities, movement disorders, obsessive-compulsive disorder,personality disorder, sleeping disorder, delirium, amyotrophic lateralsclerosis, developmental disorders, intellectual disability,post-traumatic stress disorder, or hepatitis.

DESCRIPTION OF EMBODIMENTS

Examples of “halogen” as used herein include fluorine, chlorine, bromineand iodine atoms.

The “C1-4 alkyl” as used herein includes methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl and isobutyl groups.

The “1 to 9 deuterated C1-4 alkyl” as used herein includes CH₂D-, CHD₂-,CD₃-, CD₃CD₂-, CD₃CD₂CD₂-, (CD₃)₂CD-, CD₃CD₂CD₂CD₂-, CD₃CD₂CD(CD₃)-,(CD₃)₃C—, and (CD₃)₂CDCD₂- and the like (D means deuterium).

The “C1-8 alkyl” as used herein includes methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl,1,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,3-dimethylbutyl, heptyl andoctyl groups.

The “C1-4 alkoxy” as used herein includes methoxy, ethoxy, propoxy,isopropoxy, butoxy, sec-butoxy, tert-butoxy and isobutoxy groups.

The “C1-4 haloalkyl” as used herein includes fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, perfluoropropyl,perfluoro(isopropyl), perfluorobutyl, perfluoro(sec-butyl),perfluoro(tert-butyl) and perfluoro(isobutyl) groups and the like.

The “C1-8 haloalkyl” as used herein includes fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichioromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, perfluoropropyl,perfluoro(isopropyl), perfluorobutyl, perfluoro(sec-butyl),perfluoro(tert-butyl), perfluoro(isobutyl), perfluoropentyl,perfluorohexyl, perfluoroheptyl and perfluorooctyl groups and the like.

Examples of “C3-5 cycloalkyl” as used herein include cyclopropyl,cyclobutyl, and cyclopentyl groups.

Examples of “C3-5 cycloalkane” as used herein include cyclopropane,cyclobutane, and cyclopentane rings.

Examples of “C3-5 cycloalkane, wherein the carbon atom of C3-5cycloalkane may be replaced with hetero atom selected from 1 to 2 N, Oand S” as used herein include cyclopropane, cyclobutane, cyclopentane,aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,tetrahydrofuran, tetrahydrothiophene, pyrazolidine, isoxazolidine,isothiazolidine, imidazolidine, oxazolidine, thiazolidine, and1,3-dioxolane rings and the like.

Examples of “C3-7 cycloalkyl” as used herein include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.0]butyl,bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl,bicyclo[2.2.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl,bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl and bicyclo[3.1.1]heptylgroups and the like.

Examples of “5 to 9 membered aromatic hetero ring” as used hereininclude “5 to 9 membered aromatic hetero ring containing 1 to 4 nitrogenatoms, 1 oxygen atoms and/or 1 sulfur atom” and the like. Examples ofthe “5 to 9 membered aromatic hetero ring containing 1 to 4 nitrogenatoms, 1 oxygen atom and/or 1 sulfur atom” include 1,2,5-oxadiazole,1,2,5-thiadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, isothiazole,1,3,4-thiadiazole, benzo[d]isothiazole, isoxazole, 1,3,4-oxadiazole,1,2,4-triazole, tetrazole, benzo[d]isoxazole,[1,2,3]triazolo[1,5-a]pyridine or [1,2,4]triazolo[4,3-a]pyridine ringsand the like.

Examples of “5 membered non-aromatic hetero ring” as used herein include“5 membered non-aromatic hetero ring containing 1 to 4 nitrogen atoms, 1oxygen atom and/or 1 sulfur atom” and the like. Examples of the “5membered non-aromatic hetero ring containing 1 to 4 nitrogen atoms, 1oxygen atoms and/or 1 sulfur atom” include 2,3-dihydro-1,2,3-oxadiazole,2,3-dihydro-1,2,3-thiadiazole, 2,3-dihydro-1,2,4-oxadiazole,2,3-dihydro-1,2,4-thiadiazole, 2,3-dihydro-1,2,5-oxadiazole,2,3-dihydro-1,2,5-thiadiazole, 2,3-dihydro-1,3,4-oxadiazole,2,3-dihydro-1,3,4-thiadiazole, 2,3-dihydro-1H-1,2,3-triazole,2,3-dihydro-1H-1,2,4-triazole, 2,3-dihydro-1H-imidazole,2,3-dihydro-1H-pyrazole, 2,3-dihydro-1H-pyrrole,2,3-dihydro-1H-tetrazole, 2,3-dihydrofuran, 2,3-dihydroisothiazole,2,3-dihydroisoxazole, 2,3-dihydrooxazole, 2,3-dihydrothiazole,2,3-dihydrothiophene, 4,5-dihydro-1,2,3-oxadiazole,4,5-dihydro-1,2,3-thiadiazole, 4,5-dihydro-1,2,4-oxadiazole,4,5-dihydro-1,2,4-thiadiazole, 4,5-dihydro-1H-1,2,3-triazole,4,5-dihydro-1H-1,2,4-triazole, 4,5-dihydro-1H-imidazole,4,5-dihydro-1H-pyrazole, 4,5-dihydro-1H-tetrazole,4,5-dihydroisothiazole, 4,5-dihydroisoxazole, 4,5-dihydrooxazole and4,5-dihydrothiazole rings and the like.

Examples of “C3-12 mono or bicyclic carbocycle” as used herein includecyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene,cyclohexene, cyclopentadiene, cyclohexadiene, benzene, indene,dihydroindene, naphthalene, dihydronaphthalene, andtetrahydronaphthalene rings and the like.

Examples of “5- to 9-membered mono or bicyclic heterocycle” as usedherein include “5- to 9-membered mono or bicyclic heterocyclescontaining 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and/or 1 sulfuratom” and the like. Examples of the “5- to 9-membered mono or bicyclicheterocycles containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atomsand/or 1 sulfur atom” include pyrrole, imidazole, triazole, tetrazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran,thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole,furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine,thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline,pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine,dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine,tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine,tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran,dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene,dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole(oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine),dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine,oxathiane, dioxolane, dioxane, dioxole, indole, benzimidazole,benztriazole, indazole, benzofuran, benzothiophene, benzoxazole,indoline, dihydrobenzimidazole, dihydrobenztriazole, dihydroindazole,dihydrobenzofuran, dihydrobenzothiophene, and dihydrobenzoxazole, ringsand the like.

In the present invention, unless particularly stated, the symbol:

indicates that the bond projects above the plane of the paper (i.e.,β-configuration), and the symbol:

In the present invention, unless particularly stated, the symbol:

indicates that the bond projects below the plane of the paper (i.e.,α-configuration), and the symbol:

indicates that the bond is the α-configuration, β-configuration or themixture of these configurations at arbitrary proportions, as apparent toa person skilled in the art.

In the present invention, R¹ is preferably, for example, Cyc1 or—CONR¹⁰R¹¹, more preferably, for example, Cyc1, and particularlypreferably, for example, 5 membered non-aromatic hetero ring.

In the present invention, Cyc1 is preferably, for example, 5 memberednon-aromatic hetero ring which may be substituted with 1 to 5 R¹², morepreferably, for example, 2,3-dihydro-1,2,5-oxadiazole,2,3-dihydro-1,2,5-thiadiazole, 4,5-dihydro-1,2,3-oxadiazole,4,5-dihydro-1,2,3-thiadiazole, 4,5-dihydro-1,2,4-oxadiazole,4,5-dihydro-1,2,4-thiadiazole, 4,5-dihydro-1H-1,2,3-triazole,4,5-dihydroisothiazole, or 4,5-dihydroisoxazole, each of which may besubstituted with 1 to 5 R¹², particularly preferably, for example,4,5-dihydro-1,2,4-oxadiazole or 4,5-dihydroisoxazole, each of which maybe substituted with 1 to 5 R², and especially preferably, for example,4,5-dihydroisoxazole which may be substituted with 1 to 5 R¹².

In the present invention, Cyc1 is also preferably, for example, 5 to 9membered aromatic hetero ring which may be substituted with 1 to 5 R¹²,more preferably, for example, 1,2,5-oxadiazole, 1,2,5-thiadiazole,1,2,4-oxadiazole, 1,2,4-thiadiazole, isothiazole, 1,3,4-thiadiazole,benzo[d]isothiazole, isoxazole, 1,3,4-oxadiazole, 1,2,4-triazole,tetrazole, benzo[d]isoxazole, [1,2,3]triazolo[1,5-a]pyridine or[1,2,4]triazolo[4,3-a]pyridine, each of which may be substituted with 1to 5 R¹², and particularly preferably, for example, isoxazole,1,3,4-oxadiazole, 1,2,4-triazole, tetrazole, benzo[d]isoxazole,[1,2,3]triazolo[1,5-a]pyridine or [1,2,4]triazolo[4,3-a]pyridine, eachof which may be substituted with 1 to 5 R².

In the present invention, R¹² is preferably, for example, (1) C1-4alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl, (4) C1-4 alkoxy, (5)phenyl which may be substituted with 1 to 3 R¹⁷, (6) C1-4 alkyl which issubstituted with phenyl, (7) dimethylamino, (8) pyridyl or (9)1-(cyclopropylmethyl)pyrazol-3-yl, or (10) two R¹² together with an atomto which these R¹² are attached may form a C3-5 cycloalkane, morepreferably, for example, (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) phenylwhich may be substituted with 1 to 3 R¹⁷, or (4) two R¹² together withan atom to which these R¹² are attached may form a C3-5 cycloalkane, andparticularly preferably, for example, C1-4 alkyl, or two R¹² togetherwith an atom to which these R² are attached may form a C3-5 cycloalkane.

In the present invention, R¹⁷ is preferably, for example, C1-4 alkyl orC1-4 alkoxy.

In the present invention, Cyc2 is preferably, for example, cyclopropane,cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene,cyclopentadiene, cyclohexadiene, benzene, pyrrole, imidazole, triazole,tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan,pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole,furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine,thiadiazine, indole, benzimidazole, benztriazole, indazole, benzofuran,benzothiophene, benzoxazole, indoline, dihydrobenzimidazole,dihydrobenztriazole, dihydroindazole, dihydrobenzofuran,dihydrobenzothiophene, or dihydrobenzoxazole, each of which may besubstituted with 1 to 5 R¹³, and more preferably, for example,cyclopropane, benzene, pyridine, thiophene, thiazole, or indoline, eachof which may be substituted with 1 to 5 R¹³.

In the present invention, R¹⁰ is preferably, for example, isopropyl,tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl,1-(trifluoromethyl)cyclopropyl or 1-cyanocyclopropyl.

In the present invention, R¹³ is preferably, for example, C1-4 alkyl orC1-4 alkoxy.

In the present invention, R¹¹ is preferably, for example, a hydrogenatom or C1-4 alkyl.

In the present invention, R² is preferably, for example, a hydrogen atomor C1-4 alkyl.

In the present invention, R³ is preferably, for example, a hydrogen atomor C1-4 alkyl.

In the present invention, R⁴ is preferably, for example, a hydrogen atomor C1-4 alkyl.

In the present invention, R⁵ is preferably, for example, a hydrogen atomor C1-4 alkyl.

In the present invention, R⁶ is preferably, for example, a hydrogen atomor C1-4 alkyl.

In the present invention, R⁷ is preferably, for example, a hydrogen atomor C1-4 alkyl.

In the present invention, R⁸ is preferably, for example, a hydrogen atomor C1-4 alkyl.

In the present invention, R⁹ is preferably, for example, imidazole whichmay be substituted with 1 to 3 R¹⁴.

In the present invention, R⁹ is also preferably, for example, pyrazolewhich may be substituted with 1 to 3 R¹⁵.

In the present invention, R¹⁴ is preferably, for example, (1) C1-8alkyl, (2) C3-7 cycloalkyl which may be substituted with C1-4 alkyl, (3)C1-8 alkyl which is substituted with Cyc3 which may be substituted with1 to 3 R¹⁶ or (4) C1-8 alkyl which is substituted with phenoxy, and morepreferably, for example, (1) C1-8 alkyl or (2) C3-7 cycloalkyl which maybe substituted with C1-4 alkyl.

In the present invention, Cyc3 is preferably, for example, phenyl orC3-7 cycloalkyl.

In the present invention, R¹⁶ is preferably, for example, C1-4 alkyl orcyano.

In the present invention, R₁₅ is preferably, for example, (1) C1-8alkyl, (2) C3-7 cycloalkyl which may be substituted with C1-4 alkyl, (3)C1-8 alkyl which is substituted with Cyc3 which may be substituted with1 to 3 R²¹, and more preferably, for example, (1) C1-8 alkyl or (2) C3-7cycloalkyl which may be substituted with C1-4 alkyl.

In the present invention, Cyc4 is preferably, for example, phenyl orC3-7 cycloalkyl.

In the present invention, R²¹ is preferably, for example, C1-4 alkyl orcyano.

In the present invention, examples of the general formula (I) preferablyinclude the general formula (I-1A):

wherein all symbols have the same meanings as above,

In the present invention, examples of the general formula (I) preferablyinclude the general formula (I-1):

wherein all symbols have the same meanings as above,

the general formula (I-1A-1):

wherein R² represents a hydrogen atom, or C1-4 alkyl;

R¹⁴ represents (1) C1-8 alkyl, (2) C3-7 cycloalkyl which may besubstituted with C1-4 alkyl, or (5) C1-8 alkyl which is substituted withphenoxy;

wherein R¹²⁻¹ and R¹²⁻² independently represent C1-4 alkyl; and

R¹²⁻¹ and R¹²⁻² together with an atom to which the R¹²⁻¹ and R¹²⁻² arebound may form C3-5 cycloalkane;

the general formula (I-2):

wherein all symbols have the same meanings as above,

the general formula (I-2-1):

wherein R² represents a hydrogen atom, C1-4 alkyl, halogen or C1-4alkoxy;

R¹⁵ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

wherein R¹²⁻¹ and R¹²⁻² independently represent C1-4 alkyl; and

R¹²⁻¹ and R¹²⁻² together with an atom to which the R¹²⁻¹ and R¹²⁻² arebound may form C3-5 cycloalkane;

the general formula (I-3A):

wherein all symbols have the same meanings as above,

the general formula (I-3):

wherein all symbols have the same meanings as above,

the general formula (I-4):

wherein all symbols have the same meanings as above,

the general formula (I-5):

wherein R^(12H) represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C3-7cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may besubstituted with 1 to 3 R¹⁷, (7) C1-4 alkyl which is substituted withphenyl, (8) dimethylamino, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl, and other symbols have the samemeanings as above,

the general formula (I-6):

wherein all symbols have the same meanings as above,

the general formula (I-7):

wherein all symbols have the same meanings as above,

the general formula (I-7-1):

wherein R¹⁴ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R^(12H1) represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted with 1to 3 R¹⁷, (7) C1-4 alkyl which is substituted with phenyl, (8)dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl)pyrazol-3-yl;preferably, R^(12H1) represents (2) CL-4 alkyl, (3) C3-7 cycloalkyl, (4)C1-4 haloalkyl, (6) phenyl which may be substituted with 1 to 3 R¹⁷, (7)C1-4 alkyl which is substituted with phenyl, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl;

R^(12H2) represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C3-7cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may besubstituted with 1 to 3 R¹⁷, (7) C1-4 alkyl which is substituted withphenyl, (8) dimethylamino, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl; preferably, R^(12H2) represents (1) ahydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl whichis substituted with phenyl, (8) dimethylamino;

and R¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen.

the general formula (I-8):

wherein all symbols have the same meanings as above,

the general formula (I-8-1):

wherein R¹⁵ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R^(12H1) represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted with 1to 3 R¹⁷, (7) C1-4 alkyl which is substituted with phenyl, (8)dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl)pyrazol-3-yl;preferably, R^(12H1) represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4)C1-4 haloalkyl, (6) phenyl which may be substituted with 1 to 3 R¹⁷, (7)C1-4 alkyl which is substituted with phenyl, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl;

R^(12H2) represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C3-7cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may besubstituted with 1 to 3 R¹⁷, (7) C1-4 alkyl which is substituted withphenyl, (8) dimethylamino, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl; preferably, R^(12H2) represents (1) ahydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl whichis substituted with phenyl, (8) dimethylamino;

and R¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen.

the general formula (I-9):

wherein all symbols have the same meanings as above,

the general formula (I-10):

wherein all symbols have the same meanings as above,

the general formula (I-11):

wherein all symbols have the same meanings as above,

the general formula (I-11-1):

wherein R¹⁴ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R^(12H1) represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted with 1to 3 R¹⁷, (7) C1-4 alkyl which is substituted with phenyl, (8)dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl)pyrazol-3-yl;preferably, R^(12H1) represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4)C1-4 haloalkyl, (6) phenyl which may be substituted with 1 to 3 R¹⁷, (7)C1-4 alkyl which is substituted with phenyl, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl;

R^(12H2) represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C3-7cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may besubstituted with 1 to 3 R¹⁷, (7) C1-4 alkyl which is substituted withphenyl, (8) dimethylamino, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl; preferably, R^(12H2) represents (1) ahydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl, (7) CL-4 alkyl whichis substituted with phenyl, (8) dimethylamino; and R⁷ represents C1-4alkyl, C1-4 alkoxy or halogen.

the general formula (I-12):

wherein all symbols have the same meanings as above,

the general formula (I-12-1):

wherein R¹⁵ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R^(12H1) represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) CL-4haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted with 1to 3 R¹⁷, (7) C1-4 alkyl which is substituted with phenyl, (8)dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl)pyrazol-3-yl;preferably, R^(12H1) represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4)C1-4 haloalkyl, (6) phenyl which may be substituted with 1 to 3 R¹⁷, (7)C1-4 alkyl which is substituted with phenyl, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl;

R^(12H2) represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C3-7cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may besubstituted with 1 to 3 R¹⁷, (7) C1-4 alkyl which is substituted withphenyl, (8) dimethylamino, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl; preferably, R^(12H2) represents (1) ahydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl whichis substituted with phenyl, (8) dimethylamino; and R⁷ represents C1-4alkyl, C1-4 alkoxy or halogen.

the general formula (I-13):

wherein all symbols have the same meanings as above,

the general formula (I-13-1):

wherein R¹⁴ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R^(12H) represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C3-7cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may besubstituted with 1 to 3 R¹⁷, (7) C1-4 alkyl which is substituted withphenyl, (8) dimethylamino, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl; preferably, R¹²H represents (1) ahydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl;

and R¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen.

the general formula (I-14):

wherein all symbols have the same meanings as above,

the general formula (I-14-1):

wherein R¹⁵ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R¹²H represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C3-7cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may besubstituted with 1 to 3 R¹⁷, (7) C1-4 alkyl which is substituted withphenyl, (8) dimethylamino, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl; preferably, R^(12H) represents (1) ahydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl;

and R¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen.

the general formula (I-15):

wherein n represents an integer of 0 to 4, and other symbols have thesame meanings as above,

the general formula (I-15-1):

wherein R¹⁴ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R¹² represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl,(4) C1-4 alkoxy, (5) phenyl which may be substituted with 1 to 3 R¹⁷,(6) C1-4 alkyl which is substituted with phenyl, (7) dimethylamino, (8)pyridyl or (9) 1-(cyclopropylmethyl)pyrazol-3-yl;

n represents an integer of 0 to 4, preferably, n is 0;

and R¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen.

the general formula (I-16):

wherein all symbols have the same meanings as above,

the general formula (I-16-1):

wherein R₁₅ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R¹² represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl,(4) C1-4 alkoxy, (5) phenyl which may be substituted with 1 to 3 R¹⁷,(6) C1-4 alkyl which is substituted with phenyl, (7) dimethylamino, (8)pyridyl or (9) 1-(cyclopropylmethyl)pyrazol-3-yl;

n represents an integer of 0 to 4, preferably, n is 0;

and R¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen.

the general formula (I-17):

wherein all symbols have the same meanings as above,

the general formula (I-17-1):

wherein R¹⁴ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R¹² represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) CL-4 haloalkyl,(4) C1-4 alkoxy, (5) phenyl which may be substituted with 1 to 3 R¹⁷,(6) C1-4 alkyl which is substituted with phenyl, (7) dimethylamino, (8)pyridyl or (9) 1-(cyclopropylmethyl)pyrazol-3-yl;

n represents an integer of 0 to 4, preferably, n is 0;

and R¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen;

the general formula (I-18):

wherein all symbols have the same meanings as above,

the general formula (I-18-1):

wherein R¹⁵ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R¹² represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl,(4) C1-4 alkoxy, (5) phenyl which may be substituted with 1 to 3 R¹⁷,(6) C1-4 alkyl which is substituted with phenyl, (7) dimethylamino, (8)pyridyl or (9) 1-(cyclopropylmethyl)pyrazol-3-yl; preferably, R¹²represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl, (4)C1-4 alkoxy,

n represents an integer of 0 to 4, preferably, n is 1;

and R¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen.

the general formula (I-19):

wherein all symbols have the same meanings as above,

the general formula (I-20):

wherein all symbols have the same meanings as above,

the general formula (I-21):

wherein m represents an integer of 0 to 2, and other symbols have thesame meanings as above,

the general formula (I-21-1):

wherein R¹⁴ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R¹³ represents C1-4 alkyl, C1-4 alkoxy or halogen; and

m represents an integer of 0 to 2.

the general formula (I-22):

wherein all symbols have the same meanings as above,

the general formula (I-23):

wherein all symbols have the same meanings as above,

the general formula (I-24):

wherein all symbols have the same meanings as above,

the general formula (I-25):

wherein all symbols have the same meanings as above,

the general formula (I-26):

wherein all symbols have the same meanings as above,

the general formula (I-27):

wherein R^(13H) represents a hydrogen atom, C1-4 alkyl, C1-4 alkoxy orhalogen, and other symbols have the same meanings as above,

the general formula (I-28):

wherein all symbols have the same meanings as above,

the general formula (I-29):

wherein all symbols have the same meanings as above,

the general formula (I-30):

wherein all symbols have the same meanings as above,

the general formula (I-31):

wherein all symbols have the same meanings as above,

the general formula (I-32):

wherein all symbols have the same meanings as above,

the general formula (I-33):

wherein all symbols have the same meanings as above,

the general formula (I-33-1):

wherein R¹⁴ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R^(12H1) represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1-4haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted with 1to 3 R¹⁷, (7) C1-4 alkyl which is substituted with phenyl, (8)dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl)pyrazol-3-yl;preferably, R^(12H1) represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4)C1-4 haloalkyl, (6) phenyl which may be substituted with 1 to 3 R¹⁷, (7)C1-4 alkyl which is substituted with phenyl, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl;

R^(12H2) represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C3-7cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may besubstituted with 1 to 3 R¹⁷, (7) C1-4 alkyl which is substituted withphenyl, (8) dimethylamino, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl; preferably, R^(12H2) represents (1) ahydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl whichis substituted with phenyl, (8) dimethylamino;

and R¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen;

the general formula (I-34):

wherein all symbols have the same meanings as above,

the general formula (I-34-1):

wherein R¹⁵ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R^(12H1) represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C14haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted with 1to 3 R¹⁷, (7) C1-4 alkyl which is substituted with phenyl, (8)dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl)pyrazol-3-yl;preferably, R^(12H)1 represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4)C1-4 haloalkyl, (6) phenyl which may be substituted with 1 to 3 R¹⁷, (7)C1-4 alkyl which is substituted with phenyl, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl;

R^(12H2) represents (1) a hydrogen atom, (2) C1-4 alkyl, (3) C3-7cycloalkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may besubstituted with 1 to 3 R¹⁷, (7) C1-4 alkyl which is substituted withphenyl, (8) dimethylamino, (9) pyridyl or (10)1-(cyclopropylmethyl)pyrazol-3-yl; preferably, R^(12H2) represents (1) ahydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl whichis substituted with phenyl, (8) dimethylamino;

and R¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen;

the general formula (I-35):

wherein all symbols have the same meanings as above,

the general formula (I-35-1):

wherein R² represents a hydrogen atom, C1-4 alkyl, halogen or C1-4alkoxy;

R¹⁴ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R¹⁰ represents C1-8 alkyl, or C1-8 haloalkyl, preferably, R¹⁰ representsisopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl; and

R¹¹ represents a hydrogen atom or C1-4 alkyl;

the general formula (I-36):

wherein all symbols have the same meanings as above;

and the general formula (I-36-1-1):

wherein R² represents a hydrogen atom, C1-4 alkyl, halogen or C1-4alkoxy;

R¹⁵ represents (1) C1-8 alkyl, or (3) C1-8 haloalkyl;

R¹⁰ represents C1-8 alkyl, or C1-8 haloalkyl, preferably, R¹⁰ representsisopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl; and

R¹¹ represents a hydrogen atom or C1-4 alkyl.

In the present invention, examples of the general formula (I) preferablyinclude the general formula (I-37):

wherein all symbols have the same meanings as above.

In the present invention, examples of the general formula (I) preferablyinclude the general formula (I-01):

wherein all symbols have the same meanings as above.

In the present invention, examples of the general formula (I) preferablyinclude the general formula (I-02):

wherein all symbols have the same meanings as above.

In the present invention, the stereo configuration of substituentscorresponding to the substituents represented by R¹, R³ and R⁴ on3-azabicyclo[3.1.0]hexane ring of the general formulae (I-1) to (I-36)is preferably in the same direction, like the general formula (I-37).

In the present invention, or in the general formula (I) or (I-1), thecompound is preferably, for example:

-   (1)    [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone;-   (2)    [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone;-   (3)    (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]methanone;-   (4)    (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone;-   (5)    {1-[(2S)-butan-2-yl]-1H-imidazol-4-yl}[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone;-   (6)    [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone;-   (7)    (1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone;-   (8)    (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone    or-   (9)    [1-(1-methylcyclopropyl)-1H-imidazol-4-yl][(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone;    or a salt thereof.

In the present invention, or in the general formula (I) or (1-2), thecompound is also preferably, for example:

-   (1)    [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone;-   (2)    (5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone;-   (3)    [5-(1-cyclopropylethyl)-1H-pyrazol-3-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone;-   (4)    [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone    or-   (5)    (5-cyclopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone    or a salt thereof.

In the present invention, or in the general formula (I) or (1-3), thecompound is also preferably, for example:

-   (1)    (1R,5S,6r)-N-tert-butyl-6-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide;-   (2)    (1R,5S,6r)-N-tert-butyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide;-   (3)    (1R,5S,6r)-N-(propan-2-yl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide    or-   (4)    (1R,5S,6r)-N-(1-cyanocyclopropyl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide    or a salt thereof.

In the present invention, or in the general formula (I) or (I-4), thecompound is also preferably, for example:

-   (1)    (1R,5S,6r)-N-(propan-2-yl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide;-   (2)    (1R,5S,6r)-N-tert-butyl-6-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide;-   (3)    (1R,5S,6r)-N-tert-butyl-N-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide    or-   (4)    (1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide,    or a salt thereof.

[Isomers]

The present invention encompasses all isomers unless otherwiseparticularly stated. For example, alkyl groups, alkoxy groups and thelike include linear and branched groups. Moreover, the present inventionencompasses isomers for double bonds, rings and condensed rings(E-forms, Z-forms, cis forms and trans forms), isomers due toasymmetrical carbon atoms (R and S forms, α and β configurations,enantiomers and diastereomers), optically active substances havingoptical rotating activity (D, L, d and 1 forms), polar substances whichcan be separated by chromatography (high polarity substances and lowpolarity substances), equilibrium compounds, rotamers, mixtures thereofat arbitrary proportions and racemic mixtures. The present inventionalso encompasses tautomers.

[Salt and Solvate]

A salt of the compound represented by the general formula (I) disclosedherein encompasses all pharmacologically acceptable salts. Thepharmacologically acceptable salt is preferably a water-soluble saltwith low toxicity. Examples of appropriate salts include acid additionsalts (such as inorganic acid salt [examples: hydrochloride,hydrobromide, hydroiodide, sulphate, phosphate, nitrate and the like],organic acid salts [examples: acetate, trifluoroacetate, lactate,tartrate, oxalate, fumarate, maleate, benzoate, citrate,methanesulphonate, ethanesulphonate, benzenesulphonate,toluenesulphonate, isethionate, glucuronate, gluconate and the like],salts with acidic natural amino acids [examples: aspartate, glutamateand the like] and the like) and the like.

A salt also encompasses quaternary ammonium salts. The quaternaryammonium salt represents a compound represented by the general formula(I) in which a nitrogen atom thereof is quaternised with an Ra group.The RY group as used herein represents, for example, a C1-8 alkyl groupwhich may be substituted with a phenyl group.

The compound represented by the general formula (I) can be converted tothe salt, N-oxide and solvate according to well-known methods.

The N-oxide of the compound represented by the general formula (I)represents the compound represented by the general formula (I) in whicha nitrogen atom is oxidized. The N-oxide may form salts such as acidaddition salts as described above.

The compound represented by the general formula (I), a salt thereof oran N-oxide thereof may form a solvate with, for example, water or analcoholic solvent (such as ethanol). The solvate preferably has lowtoxicity and is water soluble.

The compound represented by the general formula (I) and a salt thereofmay be in the form of without forming a solvate or may be in the form ofa solvate with a pharmaceutically acceptable solvent such as water andethanol. The solvate is preferably a hydrate. The compound representedby the general formula (I) or a salt thereof can be converted to thesolvate according to well-known methods.

The compound represented by the general formula (I) and a salt thereofmay form a co-crystal with an appropriate co-crystal former. Theco-crystal is preferably pharmaceutically acceptable as formed with apharmaceutically acceptable co-crystal former.

A co-crystal is defined to be a crystal typically formed of 2 or moremolecules by intermolecular interaction that is not ionic bonding. Theco-crystal may be a complex of a neutral molecule and a salt.Co-crystals may be prepared according to well-known methods such as meltcrystallization, recrystallization from a solvent or physical grindingof components together. Appropriate co-crystal formers include thosedisclosed in WO 2006/007448.

In the present invention, all the recitations on the present compoundencompass the compound represented by the general formula (I), a saltthereof, a solvate (such as hydrate) thereof, an N-oxide thereof or aco-crystal thereof, or a solvate (such as hydrate), N-oxide orco-crystal of a salt of the compound represented by the general formula(I).

Namely, in the present invention, the compound represented by thegeneral formula (I) or a salt thereof encompasses a solvate (such ashydrate), N-oxide or co-crystal of the compound represented by thegeneral formula (I) or a solvate (such as hydrate), N-oxide orco-crystal of a salt of the compound represented by the general formula(I).

[Prodrug]

The prodrug of the compound represented by the general formula (I)refers to a compound which is converted in vivo to the compoundrepresented by the general formula (I) by the reaction with enzymes,gastric acid and the like. Examples of the prodrug of the compoundrepresented by the general formula (I) include, when the compoundrepresented by the general formula (I) has an amino group, compounds inwhich the amino group is acylated, alkylated or phosphorylated (e.g.compounds represented by the general formula (I) in which the aminogroup thereof is converted to eicosanoyl, alanyl, pentylaminocarbonyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl,pyrrolidylmethyl, pivaloyloxymethyl, acetoxymethyl, tert-butyl or thelike); when the compound represented by the general formula (I) has ahydroxy group, compounds in which the hydroxy group is acylated,alkylated, phosphorylated or converted to borate (e.g. compoundsrepresented by the general formula (I) in which the hydroxy groupthereof is converted to acetyl, palmitoyl, propanoyl, pivaloyl,succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl or the like) andthe like. The prodrug of the compound represented by the general formula(I) may be the one which is converted to the compound represented by thegeneral formula (I) under the physiological condition such as thosedisclosed in “Iyakuhin no Kaihatsu”, vol. 7 “Bunshi Sekkei”, p. 163-198,1990, Hirokawa Shoten Co. The prodrug of the compound represented by thegeneral formula (I) can be produced by the methods well known per se.The prodrug of the compound represented by the general formula (I) mayform, similarly to the compound represented by the general formula (I),for example, salts such as acid addition salts, or may form solvateswith water or an alcoholic solvent (such as ethanol).

[Labelled Compound]

In the present invention, the compound represented by the generalformula (I), or a salt thereof encompasses a so-called labelled compoundin which some or all atoms constituting the compound is substituted withan isotope thereof. The labelled compound may be produced according tothe methods well known per se. Examples of isotopes which may be usedfor labelling suitably include, but are not limited to, ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁶N, ¹⁷O, ¹⁸O, ³⁵S, ³⁶Cl, ⁷⁷Br, ¹²⁵I and the like.

[Production Method] [Method for Producing Compound of the PresentInvention]

The compound represented by the general formula (I) or a salt thereofmay be produced by well-known methods, for example, methods described inthe following methods represented in Scheme I to XII, methods equivalentto these methods, methods described in Examples, methods equivalent tothose described in Examples, or methods described in ComprehensiveOrganic Transformations: A Guide to Functional Group Preparations, 2ndEdition (Richard C. Larock, John Wiley & Sons Inc., 1999), methodsadapted from the foregoing or methods combining the foregoing withoutlimitation. In the production methods described hereinbelow, rawmaterial compounds may be those forming salts. Examples of the saltsinclude those mentioned above as salts of the compound represented bythe general formula (I).

Wherein the compound represented by the general formula (I) can beproduced by subjecting the compound represented by the general formula(III) and the compound represented by the general formula (IV) to anamidation reaction.

The amidation is known. For example, it includes the method

(1) via an acyl halide,(2) via a mixed acid anhydride,(3) using a condensing agent.

These methods are explained as follows.

(1) The method via an acyl halide may be carried out, for example, byreacting a carboxylic acid with an acyl halide (e.g., oxalyl chloride orthionyl chloride) in an organic solvent (e.g., chloroform,dichloromethane, diethyl ether or tetrahydrofuran) or without a solventat about −20° C. to reflux temperature. And then, the obtained acylhalide derivative may be reacted with an amine in an organic solvent(e.g., chloroform, dichloromethane, diethyl ether or tetrahydrofuran) inthe presence of a base (e.g., pyridine, triethylamine, dimethylaniline,dimethylaminopyridine or diisopropylethylamine etc.) at about 0 to 40°C.

As an alternative, the obtained acyl halide derivative may be reactedwith an amine in an organic solvent (e.g., dioxane, tetrahydrofuran)using an alkaline aqueous solution (e.g., sodium hydrogen carbonate,sodium hydroxide) at about −78 to 40° C.

(2) The method via a mixed acid anhydride may be carried out, forexample, by reacting a carboxylic acid with an acyl halide (e.g.,pivaloyl chloride, p-toluenesulfonyl chloride or methanesulfonylchloride) or an acid derivative (e.g., ethyl chloroformate or isobutylchloroformate) in an organic solvent (e.g., chloroform, dichloromethane,diethyl ether, tetrahydrofuran) or without a solvent, in the presence ofa base (e.g., pyridine, triethylamine, dimethylaniline,dimethylaminopyridine or diisopropylethylamine) at about 0 to 40° C. Andthen the obtained mixed acid anhydride derivative may be reacted with anamine in an organic solvent (e.g., chloroform, methylene chloride,diethyl ether or tetrahydrofuran), at about 0 to 40° C.(3) The method using a condensing agent may be carried out, for example,by reacting a carboxylic acid with amine in an organic solvent (e.g.,chloroform, dichloromethane, dimethylformamide, diethyl ether ortetrahydrofuran) or without a solvent, in the presence or absence of abase (e.g., pyridine, triethylamine, dimethylaniline ordimethylaminopyridine), using a condensing agent (e.g., 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide(EDC), 1,1′-carbodiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,or 1-propanephosphonic acid cyclic anhydride (PPA)), in the presence orabsence of 1-hydroxybenzotriazole (HOBt), at about 0 to 40° C.

The reaction described in (1), (2) and (3) may be carried out under aninert gas (e.g., argon, nitrogen) to avoid water in order to obtain apreferable result.

The compound represented by the general formula (III) can be produced bysubjecting the compound represented by the general formula (II) to adeprotection reaction of protecting group of amino group.

P in the general formula (II) is represented a protecting group of aminogroup.

P includes such as benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc),allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc),trifluoroacetyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn),p-methoxybenzyl, benzyloxymethyl (BOM) or 2-(trimethylsilyl)ethoxymethyl(SEM) etc.

Deprotection reaction of protecting group of amino group can beconducted by suitable condition of each protective group.

For example, a deprotection of tert-butoxycarbonyl (Boc) group can beconducted with acidic reagent (e.g., HCl/dioxane, TFA or MsOH) insolvent (e.g., dioxane or dichloromethane) at 0° C. to 40° C.

For example, a deprotection of benzyloxycarbonyl (Z) group can beconducted by hydrogenation condition such as hydrogen and catalytic Pd-Cin solvent (e.g., MeOH or EtOH etc.) at 20° C. to 60° C.

Deprotection reaction of protecting group of amino group is well knownand well described in T. W. Greene, Protective Groups in OrganicSynthesis, Wiley, New York, 1999.

Wherein R¹ in the general formula (II in Scheme I represents:

and

the general formula (II) can be described as the general formula (II)-1in Scheme II

The compound represented by the general formula (II)-1 can be producedby subjecting the compound represented by the general formula (VII) andthe compound represented by the general formula (VIII) to an isoxazolinecyclization reaction.

An isoxazoline cyclization reaction can be carried out with base (e.g.,trimethylamine or DIPEA) and solvent (e.g., DMF etc.) at 0° C. to 80° C.

The compound represented by the general formula (VII) can be produced bysubjecting the compound represented by the general formula (VI) to achlorination reaction.

A chlorination reaction can be carried out with a chlorination reagent(e.g., N-chlorosuccinimide) in solvent (e.g., DMF etc.) at about 0° C.to 40° C.

The compound represented by the general formula (VI) can be produced bysubjecting the compound represented by the general formula (V) to anoxime forming reaction.

An oxime forming reaction can be carried out with hydroxylaminehydrochloride, potassium acetate and acetic acid in solvent (e.g., EtOHetc.) at about 20° C. to 40° C.

Wherein R¹ in the general formula (II) in Scheme I represents

and

the general formula (II) can be described as the general formula (II)-2in Scheme III.

The compound represented by the general formula (II)-2 can be producedby subjecting the compound represented by the general formula (IX) andthe compound represented by the general formula (X) to an amidationreaction.

An amidation can be carried out by the same method described above forthe preparation of the general formula (I) in Scheme I.

The compound represented by the general formula (II)-2 can be producedby subjecting the compound represented by the general formula (XII) andthe compound represented by the general formula (XIII) to an alkylationreaction.

An alkylation reaction can be carried out with base (e.g., sodiumhydride, potassium hydride, lithium hydride, sodium methoxide, sodiumethoxide, potassium tert-butoxide, butyl lithium, LDA, LHMDS, NaHMDS,KHMDS etc.) in solvent (e.g., THF, DMF, DMA, diethyl ether etc) at −78°C. to 40° C.

The compound represented by the general formula (XII) can be produced bysubjecting the compound represented by the general formula (IX) and thecompound represented by the general formula (XI) to an amidationreaction.

An amidation can be carried out by the same method described above forthe preparation of the general formula (I) in Scheme I.

Wherein R¹ in the general formula (II) in Scheme I represents

and

the general formula (II) can be described as the general formula (II)-3in Scheme IV.

The compound represented by the general formula (II)-3 can be producedby subjecting the compound represented by the general formula (XV) to anoxidation reaction of hydroxyl group.

The oxidation of hydroxyl group is known. For example, it includes themethod

(1) Dess-Martin oxidation(2) DMSO oxidation(3) Chromium reagent oxidation.

These methods are explained as follows.

(1) The method of Dess-Martin oxidation can be carried out withDess-Martin Periodinane in solvent (for example methylene chloride) at0° C. to 40° C.(2) The method of DMSO oxidation can be carried out with DMSO and itsactivator (e.g., oxalyl chloride, thionyl chloride or sulfur trioxidepyridinium complex etc.) and base (for example trimethylamine or DIPEAetc) at −78° C. to 40° C.(3) The method of chromium reagent oxidation is carried out withchromium oxidant (for example PCC or PDC) in solvent (for exampledichloromethane) at −20° C. to 40° C.

The compound represented by the general formula (XV) can be produced bysubjecting the compound represented by the general formula (V) and thecompound represented by the general formula (XIV) to an additionreaction.

Wherein M in the general formula (XIV) represents metal (e.g., Li, Na orK) or metal halide (MgCl, MgBr, MgI, ZnCl, ZnBr or ZnI).

An addition reaction can be carried out in solvent (e.g., THF) at −78°C. to 0° C. under inert atmosphere (e.g., dry nitrogen or argon).

Wherein R¹ in the general formula (II) in Scheme I represents

and

the general formula (II) can be described as the general formula (II)-4and (II)-4a in Scheme V.

The compound represented by the general formula (II)-4 can be producedby subjecting the compound represented by the general formula (VII) andthe compound represented by the general formula (XVI) to an isoxazolecyclization reaction.

An isoxazole cyclization reaction can be carried out with base (forexample trimethylamine etc.) in solvent (for example dichloromethaneetc.) at −20° C. to 40° C.

The compound represented by the general formula (II)-4a can be producedby subjecting the compound represented by the general formula (XVII) andthe compound represented by the general formula (XVIII) to a couplingreaction.

The coupling reaction is well known and can be carried out by, forexample, reacting in an organic solvent (examples: benzene, toluene,dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile,dimethoxyethane, acetone or mixed solvents thereof), with a base(examples: sodium ethylate, sodium hydroxide, potassium hydroxide,triethylamine, sodium carbonate, sodium hydrogen carbonate, potassiumcarbonate, caesium carbonate, thallium carbonate, tripotassiumphosphate, caesium fluoride, barium hydroxide, tetrabutylammoniumfluoride and the like) or aqueous solutions thereof or mixtures thereofin the presence of a catalyst (examples:bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)((A-taPhos)₂PdCl₂), tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄),bis(triphenylphosphine)palladium dichloride (PdCl₂(PPh₃)₂), palladiumacetate (Pd(OAc)₂), palladium black,1,1′-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl₂(dppf)₂),diallylpalladium dichloride (PdCl₂(allyl)₂), iodophenylbis(triphenylphosphine)palladium (PhPdI(PPh₃)₂) and the like) at roomtemperature to 150° C.

The compound represented by the general formula (XVII) can be producedby subjecting the compound represented by the general formula (II)-4 toa bromination reaction.

A bromination reaction can be carried out with bromination reagent(e.g., NBS or bromine etc.) in solvent (for example DMF etc.) at −20° C.to 40° C.

Wherein R¹ in the general formula (II) in Scheme I represents

the general formula (II) can be described as the general formula (II)-5in Scheme VI.

The compound represented by the general formula (II)-5 can be producedby subjecting the compound represented by the general formula (VII) andthe compound represented by the general formula (XIX) to a1,2,4-oxadiazoline cyclization reaction.

A 1,2,4-oxadiazoline cyclization reaction can be carried out with base(for example trimethylamine etc.) in solvent (for example THF, tolueneor DMF etc.) at 0° C. to 40° C.

Wherein R¹ in the general formula (II) in Scheme I represents

and

the general formula (II) can be described as the general formula (II)-6in Scheme VII.

The compound represented by the general formula (II)-6 can be producedby subjecting the compound represented by the general formula (XXII) toa 1,3,4-oxadiazole cyclization reaction.

A 1,3,4-oxadiazole cyclization reaction can be carried out withdehydrating agent (e.g., POCl₃ etc.) at 80° C. to 120° C.

The compound represented by the general formula (XXII) can be producedby subjecting the compound represented by the general formula (XX) andthe compound represented by the general formula (XXI)-1 or (XXI)-2 to anamidation reaction.

An amidation can be carried out by the same method described above forthe preparation of the general formula (I) in Scheme I.

The compound represented by the general formula (XX) can be produced bysubjecting the compound represented by the general formula (IX) to anamidation reaction.

An amidation can be carried out by the same method described above forthe preparation of the general formula (I) in Scheme I.

Wherein R¹ in the general formula (II) in Scheme I represents

and

the general formula (II) can be described as the general formula (II)-7in Scheme VIII.

The compound represented by the general formula (II)-7 can be producedby subjecting the compound represented by the general formula (II)-6 andthe compound represented by the general formula (XXIII) to a replacementreaction.

A replacement reaction can be carried out with acidic catalyst (e.g.,TsOH etc.) in solvent (e.g., xylene etc.) at 120° C. to 150° C.

The compound represented by the general formula (II)-7 can be producedby subjecting the compound represented by the general formula (XXIV) andthe compound represented by the general formula (XXIII) to a1,3,4-triazole cyclization reaction.

A 1,3,4-triazole cyclization reaction can be carried out with aceticacid at 0° C. to 100° C.

The compound represented by the general formula (XXIV) can be producedby subjecting and the compound represented by the general formula (XX)to a hydrazonoformamide formation reaction.

A hydrazonoformamide formation reaction can be carried out with1,1-dimethoxy-N,N-dimethylmethanamine in solvent (e.g., acetonitrile orDMF etc.) at 100° C. to 120° C.

Wherein R¹ in the general formula (II) in Scheme I represents

and

the general formula (II) can be described as the general formula (II)-8in Scheme IX.

The compound represented by the general formula (II)-8 can be producedby subjecting the compound represented by the general formula (XXVI) toa dehydrative tetrazole cyclization reaction.

A dehydrative tetrazole cyclization reaction can be carried out withTf₂O and TMSN₃ in solvent (e.g., dichloromethane etc.) at 0° C. to 30°C.

The compound represented by the general formula (XXVI) can be producedby subjecting the compound represented by the general formula (IX) andthe compound represented by the general formula (XXV) to an amidationreaction.

An amidation can be carried out by the same method described above forthe preparation of the general formula (I) in Scheme I.

Wherein R¹² represents H, the compound represented by the generalformula (II)-8 can be produced by subjecting the compound represented bythe general formula (XXVIII) to a tetrazole cyclization reaction.

A tetrazole cyclization reaction can be carried out with NaN₃ and NH₄Clin solvent (e.g., DMF etc.) at 100° C. to 140° C.

The compound represented by the general formula (XXVIII) can be producedby subjecting the compound represented by the general formula (XXVII) toa nitrile formation reaction.

A nitrile formation reaction can be carried out with dehydration agent(e.g., cyanuric chloride, thionyl chloride or P₂O₅ etc.) in solvent(e.g., DMF, benzene, toluene or xylene etc.) at 100° C. to 140° C.

The compound represented by the general formula (XXVII) can be producedby subjecting the compound represented by the general formula (IX) andammonia to an amidation reaction.

An amidation can be carried out by the same method described above forthe preparation of the general formula (I) in Scheme I.

Wherein R¹ in the general formula (II) in Scheme I represents

and

the general formula (II) can be describe as the general formula (II)-9in Scheme X.

The compound represented by the general formula (II)-9 can be producedby subjecting the compound represented by the general formula (XXX) to a[1,2,4]triazolo[4,3-a]pyridine cyclization reaction.

A [1,2,4]triazolo[4,3-a]pyridine cyclization reaction can be carried outwith Burgess reagent in solvent (e.g., acetonitrile etc.) at 100° C. to140° C.

The compound represented by the general formula (XXX) can be produced bysubjecting the compound represented by the general formula (IX) and thecompound represented by the general formula (XXIX) to an amidationreaction.

An amidation can be carried out by the same method described above forthe preparation of the general formula (I) in Scheme 1.

Wherein R¹ in the general formula (II) in Scheme I represents

and

the general formula (II) can be described as the general formula (II)-10in Scheme XI.

The compound represented by the general formula (II)-10 can be producedby subjecting the compound represented by the general formula (XXXIII)to a [1,2,3]triazolo[1,5-a]pyridine cyclization reaction.

A [1,2,4]triazolo[4,3-a]pyridine cyclization reaction can be carried outwith hydrazine hydrate at 50° C. to 70° C., followed by the treatment ofcupper acetate in solvent (e.g., ethylacetate etc.) at 20° C. to 40° C.

The compound represented by the general formula (XXXIII) can be producedby subjecting the compound represented by the general formula (XXXII) toan oxidation reaction of hydroxyl group.

An oxidation reaction of hydroxyl group can be carried out by the samemethod described above for the preparation of the general formula (II)-3in Scheme IV.

The compound represented by the general formula (XXXII) can be producedby subjecting the compound represented by the general formula (V) andthe compound represented by the general formula (XXXI) to an additionreaction.

An addition reaction can be carried out by the same method describedabove for the preparation of the general formula (XV) in Scheme IV.

Wherein the compounds represented by the general formula (IV), (VIII),(X), (XI), (XIII), (XIV), (XVI), (XVIII), (XIX), (XXI)-1, (XXI)-2,(XXIII), (XXV), (XXVII), (XXIX) and (XXXI) can be availablecommercially, or easily prepared from commercial chemicals by well-knownmethod described in, for example, Comprehensive Organic Transformations:A Guide to Functional Group Preparations, 2nd Edition (Richard C.Larock, John Wiley & Sons Inc., 1999) and the like.

Wherein the compound represented by the general formula (V) can beavailable commercially or prepared by the method described in SchemeXII.

Wherein the compound represented by the general formula (V) can beproduced by subjecting the compound represented by the general formula(XXXIX) to an oxidation reaction of hydroxyl group.

An oxidation reaction of hydroxyl group can be carried out by the samemethod described above for the preparation of the general formula (II)-3in Scheme IV.

The compound represented by the general formula (XXXIX) can be producedby subjecting the compound represented by the general formula (XXXVIII)to a protection exchange reaction.

A protection exchange reaction can be carried out with hydrogen gas, Pdcatalyst (e.g., Pd—C or Pd(OH)₂—C etc.) and (Boc)₂O in solvent (e.g.,MeOH, EtOH or THF etc.) at 20° C. to 40° C.

The compound represented by the general formula (XXXVIII) can beproduced by subjecting the compound represented by the general formula(XXXVII) to an ester reduction reaction.

An ester reduction reaction can be carried out with reductant (e.g.,LiAlH₄, DIBAL-H, Red-Al etc.) in solvent (e.g., THF, diethylether or DMEetc.) at −20° C. to 20° C.

The compound represented by the general formula (XXXVII) can be producedby subjecting the compound represented by the general formula (XXXVIII)and to an imide reduction reaction.

An imide reduction reaction can be carried out with borane reductant(e.g., BH₃ THF, BH₃ Me₂S or B₂H₆ etc.) in solvent (e.g., THF,diethylether or DME etc.) at 20° C. to 80° C.

The compound represented by the general formula (XXXVII) can be producedby subjecting the compound represented by the general formula (XXXV) andthe compound represented by the general formula (XXXVI) to acyclopropanation reaction.

A cyclopropanation reaction can be carried out with MnO₂ in solvent(e.g., dioxane etc) at 20° C. to 100° C.

The compound represented by the general formula (XXXV) can be producedby subjecting the compound represented by the general formula (XXXIV) toa hydrazone formation reaction.

A hydrazone formation reaction can be carried out with hydrazine hydrateand acetic acid in water at 0° C. to 40° C.

Wherein the compound represented by the general formula (XXXIV) and(XXXVI) can be available commercially, or easily prepared fromcommercial chemicals by well-known method described in, for example,Comprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc.,1999) and the like.

In the reactions exemplified herein, any heating means such as waterbath, oil bath, sand bath and microwave may be used.

In the reactions exemplified herein, a solid phase-supported reagentsupported on a polymer (such as polystyrene, polyacrylamide,polypropylene and polyethylene glycol) may be used, if appropriate.

The products from the reactions exemplified herein may be purified by aconventional purification means, for example, distillation under normalor reduced pressure, chromatography (such as high performance liquidchromatography, thin layer chromatography or column chromatography)using silica gel, an ion exchange resin, scavenger resin or magnesiumsilicate, or by washing or recrystallization. Purification may becarried out after each reaction step or after a series of reactions.

[Toxicity]

The present compound has low toxicity and thus can be safely used as amedicament.

[Application to Medicaments]

The present compound has KDM5 inhibitory activity, and thus can be usedas an agent for prophylaxis and/or therapy of KDM5-related diseases inmammals, particularly in humans.

Examples of such diseases include hyperproliferative disease, cancer,stroke, diabetes, hepatomegaly, cardiovascular disease, multiplesclerosis, Huntington's disease, Alzheimer's disease, cystic fibrosis,viral disease, autoimmune diseases, atherosclerosis, restenosis,psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma,allergic disorders, inflammation, neurological disorders, ahormone-related disease, conditions associated with organtransplantation, immunodeficiency disorders, destructive bone disorders,proliferative disorders, infectious diseases, conditions associated withcell death, thrombin-induced platelet aggregation, liver disease,pathologic immune conditions involving T cell activation, CNS disorders,myeloproliferative disorder, Parkinson's disease, Lewy body disease,frontotemporal lobar degeneration, mild cognitive impairment, cognitiveimpairment, cerebrovascular disease, schizophrenia, depression, anxietydisorder, bipolar disorder, autism spectrum disorder, attentiondeficit/hyperactivity disorder, learning disabilities, movementdisorders, obsessive-compulsive disorder, personality disorder, sleepingdisorder, delirium, amyotrophic lateral sclerosis, developmentaldisorders, intellectual disability, post-traumatic stress disorder, andhepatitis and the like.

Among others, the present compound is useful for prophylaxis and/ortherapy of cancer, Huntington's disease, Alzheimer's disease,Parkinson's disease, Lewy body disease, frontotemporal lobardegeneration, mild cognitive impairment, cognitive impairment,cerebrovascular disease, schizophrenia, depression, anxiety disorder,bipolar disorder, autism spectrum disorder, attentiondeficit/hyperactivity disorder, learning disabilities, movementdisorders, obsessive-compulsive disorder, personality disorder, sleepingdisorder, delirium, amyotrophic lateral sclerosis, developmentaldisorders, intellectual disability, post-traumatic stress disorder, orhepatitis. The present compound is particularly suitable for prophylaxisand/or therapy of cancer and Alzheimer's disease.

In addition to having a strong KDM5 inhibitory activity, the presentcompound is excellent in metabolic stability and can be present in thebrain at a high concentration.

Examples of test methods for evaluating the pharmacological activity ofthe present compounds include an evaluation system of improvement ofcognitive impairment in mice.

For example, improvement of cognitive impairment by the presentcompounds may be evaluated by using the following method.

Mice (16 to 23-month old male C57BL/6 mice (Charles River LaboratoriesJapan, Inc.)) are used. A test compound and its vehicle are orallyadministered once daily for 2 weeks. After that, the cognitive functionwill be assessed by the novel object recognition (NOR) test using aplastic cage (ECON cage, CL-0107, 345 mm*403 mm*177 mm, CLEA Japan,Inc.) with a video camera as the experimental apparatus. The evaluationis performed in a dark room and the light intensity is adjusted toapproximately 20 lux near the experimental apparatus. To acclimatizeanimals to the evaluation environment, the mice are moved to theevaluation room at least 1 hour prior to the start of the trial. Thestudy will be conducted over 3 days. For acclimation to the experimentalapparatus on Day 1, the mice are placed in a cage and allowed to movefreely for 10 minutes. In the acquisition trial on Day 2, two identicalobjects (familiar objects) are placed on the cage and performed in thesame way for 10 minutes. The two objects are placed apart on a lineparallel to the long side of one cage.

The distance between the object and the inner wall of the two adjacentsurfaces is 10 cm. In the test trial on Day 3, one of the objects usedin the acquisition trial is replaced by a novel object with a differentcolor and shape, and the animals behave in the same manner for 10minutes. The test trials start 24 hours (Acceptable range: 23 to 25hours) after the acquisition trials. From the video images recorded inthe test trials, the exploration time for each object is measured. Fromthe exploration time of familiar and novel objects, the totalexploration time and the novel object recognition rate are calculated bythe following equation.

Total exploration time (seconds)=Exploration Time for familiarobject+Exploration time for novel object

Recognition index (%)=100*(Exploration time for novel object/Totalexploration time)

Examples of test methods for evaluating the pharmacological activity ofthe present compounds include the clonogenic assay and the cytotoxicityassay in cancer cells. For example, efficacy of the present compounds incancer cells may be evaluated by using the following methods.

MCF-7, T47D and MBA-MB231 human breast cancer cells are purchased fromATCC with certification. Cells are cultured for at most 10-12 passages,then replaced by cells from early passages, kept in liquid nitrogensince collection. Cells are grown in adherence in high glucoseDulbecco's Modified Eagle Medium (DMEM) with 1% penicillin/streptomycin,2 mM L-glutamine, 10% previously inactivated fetal bovine serum. Cellsare maintained at 37° C. and 5% CO₂ in an incubator and routinelypassaged removing DMEM, washing with PBS and detaching them using asuitable amount of Trypsin/EDTA.

For the clonogenic assay, one hour after treatment with the compound,cells are exposed to X-ray using a MLG 300/6-D apparatus (Gilardoni) setto 200 V and 6 mA, in order to produce an equivalent absorbed dose of1cGy/s. Afterwards, cells are harvested, counted and then diluted in thegrowth medium containing the compound. Appropriate cell numbers areseeded in quadruplicate according to the doubling time of the cell lineand to radiation dose. Twenty-four hours after this seeding, the mediumwith the compound is replaced with fresh DMEM and cells are thenincubated for 14 days (enough time to allow at least six celldivisions). After this period of growth, cells are washed twice with PBSand then fixed and stained with a suitable volume of a solution made of0.3% Methylene Blue and 80% Ethanol for 30 min at room temperature.After washing cells twice with ddH2O, plates are pictured with ChemiDocXRS+ Imaging System (Bio-Rad) in colorimetric mode. Radiation-doseresponse curves to X-ray for DMSO and the compound samples arecalculated using surviving fraction. Plating efficiency and survivingfraction are calculated as follows:

Plating efficiency=number of colonies counted/number of cells plated

Surviving fraction=Plating efficiency/plating efficiency of sham sample

For the cytotoxicity assay, Cell Counting Kit-8 (#CK04, DOJINDO) is usedaccording to the manufacturer's instructions. MCF-7 T47D or MDA-MB231cell suspension (5000 cells/100 μL/well) is dispensed in a 96-wellplate. After 24 hours, the compound or DMSO is added in growth mediumand then cells are irradiated. Forty-eight hours post irradiation, 10 μLof CCK-8 solution is added to each well of the plate and incubated againfor 1 hour. The absorbance at 450 nm is read using a VICTOR2 1420 reader(Perkin Elmer).

Examples of test methods for evaluating the pharmacological activity ofthe present compounds include the primary human hepatocytes (PHH) assayfor inhibition of hepatitis B virus antigen (HbsAg). For example,efficacy of the present compounds in the PHH assay may be evaluated byusing the following methods.

Primary human hepatocytes (PHH) (Bioreclamation IVT) are plated oncollagen-coated flasks using Plating Media (Life Technologies)containing William's Medium E supplemented with 1%penicillin/streptomycin, 4 pg/mL human recombinant insulin, 2 mMGlutaMAX, 15 mM HEPES, 1 μM dexamethasone, 5% fetal bovine serum, and0.2% Antibiotic Mix. After a 4-hour incubation at 37° C., cells areswitched to Maintenance Media (Life Technologies) containing William'sMedium E supplemented with 0.5% penicillin/streptomycin, 6.25 pg/mLhuman recombinant insulin, 6.25 pg/mL human transferrin, 6.25 ng/mLselenous acid, 1.25 mg/mL bovine serum albumin, 5.35 pg/mL linoleicacid, 2 mM GlutaMAX, 15 mM HEPES, 0.1 μM dexamethasone, 2% fetal bovineserum, 2% DMSO, and 0.2% Antibiotic Mix. On the next day, PHH areinfected with 500 genome equivalent per cell of genotype D(AD38-derived) HBV in Maintenance Media supplemented with 4% PEG 8000(Promega). After 24 hour incubation, cells are washed three times withWilliam's Medium E and fed with fresh Maintenance Media. At 3 days afterinfection, infected PHH cells are seeded on 96-well plates pre-coatedwith collagen at a density of 65000 cells per well containing seriallydiluted solutions of compounds or DMSO (1% final concentration) in afinal volume of 125 μï of Maintenance Media (Life Technologies). Mediawith compounds is replenished every 2-3 days. After an incubation timeof 12 days, secreted HBsAg in the supernatant are measured using amultiplex chemiluminescent (Mesoscale discovery, MSD) assay usingcapture and detection antibody pairs specific for HBsAg. EC50 values arecalculated from the fit of the dose-response curves to a four-parameterequation.

Examples of test methods for evaluating the pharmacological activity ofthe present compounds include an evaluation system of improvement of thedepressive symptoms in the social defeat stress model. For example,efficacy of the present compounds in the social defeat model may beevaluated by using the following methods.

Eight-week-old male DBA/2 mice are used for the study. The social defeatstress is given to the mice. The test mice are placed in a highlyaggressive CD-1 mouse cage for 5 minutes. At this time, CD-1 mice willattack the test mice unilaterally (Physical Stress). After 5 minutes,CD-1 mice and test mice are separated by a transparent acrylic plate andmaintained for 24 hours (psychological stress burden). This process isdone for 5 consecutive days. The compound or vehicle is orallyadministrated 2 hours before the social defeat stress in each day. Afterthat, the social interaction test and the sucrose preference test areconducted.

For the social interaction test, CD-1 mice as a novel mouse are placedin a box of 42 cm square (Target Area). Test mice (DBA/2 mouse) areplaced in the boxes and the time spent in the target area for 3 minutesis measured by a video tracking system (Any-Maze Software). Timecontacting with a novel mouse is reduced in depressed animals.

For the sucrose preference test, bottles containing 1% sucrose solutionand normal water are given simultaneously. The amount of sucrosesolution and normal water consumed over 4 h is measured, and thepercentage of sucrose water consumed (sucrose preference) is used as anindicator of anhedonia. Animals usually prefer sweet sucrose, butanimals in the anhedonia state, a condition of depression, have reducedpreference for sucrose.

Upon using the present compound for pharmaceutical purposes, the presentcompound may be used not only as a single drug but also as a combineddrug with an additional active component, for example those listedhereinbelow, for the purposes of, for example, (1) supplementing and/orenhancement of the effect thereof for prophylaxis, therapy and/oramelioration of symptoms, (2) improvement of the kinetics andabsorption, reduction of the dosage thereof and/or (3) alleviation ofside-effects thereof.

When the present compound is used for prophylaxis and/or therapy ofAlzheimer's disease, examples of the drugs which may be used incombination with the present compound include symptomatic agents, forexample those known to modify cholinergic transmission such as M1 and M3muscarinic receptor agonists or allosteric modulators, M2 muscarinicantagonists, M4 agonists or positive allosteric modulators (PAMs),acetylcholinesterase inhibitors (such as tetrahydroaminoacridine,donepezil hydrochloride and rivastigmine), nicotinic receptor agonistsor allosteric modulators (such as α7 agonists or allosteric modulatorsor α4β2 agonists or allosteric modulators), PPAR agonists (such as PPARyagonists), 5-HT₄ receptor agonists or partial agonists, histamine H3antagonists, 5-HT₆ receptor antagonists or 5HT_(1A) receptor ligands andNMDA receptor antagonists or modulators, 5-HT_(2A) antagonists, 5-HT₇antagonists, D1 agonists or PAMs, D4 agonists or PAMs, D5 agonists orPAMs, GABA-A a5 inverse agonists or negative allosteric modulators(NAMs), GABA-A a2/3 agonists or PAMs, mGluR2 modulators (PAMs or NAMs),mGluR3 PAMs, mGluR5 PAMs, PDE 1 inhibitors, PDE 2 inhibitors, PDE 4inhibitors, PDE 5 inhibitors, PDE 9 inhibitors, PDE 10 inhibitors, GlyT1inhibitors, DAAO inhibitors, ASCI inhibitors, AMPA modulators, SIRT1activators or inhibitors, AT4 antagonists, GalR1 antagonists, GalR3ligands, adenosine A1 antagonists, adenosine A2a antagonists, a2Aantagonists or agonists, selective and unselective norepinephrinereuptake inhibitors (SNRIs), or potential disease modifying agents suchas gamma secretase inhibitors or modulators, alpha secretase activatorsor modulators, amyloid aggregation inhibitors, amyloid antibodies, tauaggregation inhibitors or tau phosphorylation/kinase inhibitors, taudephosphorylation/phosphatase activators, mitogen-activated proteinkinase kinase 4 (MKK4/MEK4/MAP2K4) inhibitors, c-Jun N-terminal kinase(JNK) inhibitors, casein kinase inhibitors, MK2 (mitogen activatedprotein kinase-activated protein kinase 2) inhibitors, MARK (microtubuleaffinity regulating kinase) inhibitors, CDK5 (cyclin dependent kinase 5)inhibitors, GSK-3 (glycogen synthase kinase-3) inhibitors andtau-tubulin kinase-1 (TTBK1) inhibitors. Further examples of such othertherapeutic agents may be calcium channel blockers, HMG-CoA(3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins) andlipid lowering agents, NGF (nerve growth factor) mimics, antioxidants,GPR3 ligands, plasmin activators, neprilysin (NEP) activators, IDE(insulin degrading enzyme) activators, melatonin MTI and/or MT2agonists, TLX/NR2E1 (tailless X receptor) ligands, GluR1 ligands, RAGE(receptor for advanced glycation end-products) antagonists, EGFR(epidermal growth factor receptor) inhibitors, FPRL-1 (formylpeptide-like receptor-1) ligands, GABA antagonists, and MICAL (moleculeinteracting with casL) inhibitors, e.g. oxidoreductase inhibitors, CB1antagonists/inverse agonists, non-steroidal anti-inflammatory drugs(NSAIDs), anti-inflammatory agents (for example agents that could beused to treat neuroinflammation either by enhancing or reducingneuroinflammation), amyloid precursor protein (APP) ligands,anti-amyloid vaccines and/or antibodies, agents that promote or enhanceamyloid efflux and/or clearance, histone deacetylase (HDAC) inhibitors,EP2 antagonists, 11-beta HSD1 (hydroxy steroid dehydrogenase)inhibitors, liver X receptor (LXR) agonists or PAMs, lipoproteinreceptor-related protein (LRP) mimics and/or ligands and/or enhancersand/or inhibitors, butyryl cholinesterase inhibitors, kynurenic acidantagonists and/or inhibitors of kynurenine aminotransferase (KAT),orphanin FQ/nociceptin (NOP)/opioid-like receptor 1 (ORL1) antagonists,excitatory amino acid transporter (EAAT) ligands (activators orinhibitors), and plasminogen activator inhibitor-1 (PAI-1) inhibitors,niacin and/or GPR109 agonists or PAMs in combination with cholesterollowering agents and/or HMGCoA reductase inhibitors (statins), dimebolinor similar agents, antihistamines, metal binding/chelating agents,antibiotics, growth hormone secretagogues, cholesterol lowering agents,vitamin E, cholesterol absorption inhibitors, cholesterol effluxpromoters and/or activators, and insulin upregulating agents, and thelike.

The present compound may alternatively be used in combination with, forexample, donepezil hydrochloride, galantamine hydrobromide, huperzine A,idebenone, levacecarnine hydrochloride, memantine hydrochloride,memantine hydrochloride/donepezil hydrochloride, proteolytic peptidefraction from porcine brain protein, rivastigmine tartrate, tacrinehydrochloride, aducanumab (genetical recombination) or the like.

The combined drug of the present compound and an additional drug may beadministered in the form of a concomitant drug containing bothcomponents in one formulation, or separate formulations may beadministered by the same or different routes of administration. It isnot necessary that separate formulations are administered simultaneouslyand separate formulations may be administered sequentially with a timedifference. When the formulations are sequentially administered, theorder or administration is not particularly limited and may beappropriately adjusted so that desired efficacy of drugs can beobtained.

The dosage of the additional drug which is used in combination with thepresent compound may be appropriately increased or decreased accordingto the clinical dosage thereof or a similar drug. The ratio between thepresent compound and the additional drug may be appropriately adjustedby considering the age and weight of the subject, the administrationmethod, the time of administration, the target disease and condition andthe like. Generally, 1 part by weight of the present compound may becombined with the additional drug in an amount ranging from 0.01 to 100parts by weight. A plurality of the additional drug may be used. Theadditional drug may be, in addition to those mentioned above, a drughaving the same mechanism as those mentioned above. Such an additionaldrug includes not only the one which has been discovered by now but alsothe one which will be discovered in future.

The dosage of the present compound may vary according to the age,weight, condition, therapeutic effect, administration method, treatmentperiod and the like. The present compound may be orally administered toan adult once to several times daily at the amount of 0.1 mg to 300 mgper administration, parenterally administered to an adult once toseveral times daily at the amount of 0.1 mg to 150 mg per administrationor intravenously and continuously administered over 1 hour to 24 hoursdaily.

As described above, the dosage may vary according to various conditions,and thus the amount less than the dosage described above may besufficient in some cases and the amount exceeding the above dosage maybe required in other cases.

When the present compound is used for prophylaxis and/or therapy of theabove diseases as a single drug or a combined drug with the additionaldrug, the present substance which is an active component is generallyformulated with a pharmaceutically acceptable carrier such as variousadditives or solvents and the obtained formulation is administeredsystemically or locally and orally or parenterally. The pharmaceuticallyacceptable carrier as used herein means a substance other than an activecomponent that is generally used for medicinal formulations. Thepharmaceutically acceptable carrier preferably does not exhibitpharmacological activity, is harmless and does not prevent thetherapeutic effect of the active component at the dosage of theformulation. The pharmaceutically acceptable carrier may also be used inorder to increase the usefulness of the active component and theformulation, to facilitate production of the formulation, to stabilizethe quality or to improve the usability. Specifically, the substancesdescribed in “Iyakuhin Tenkabutsu Jiten”, 2000, Yakuji Nippo Ltd. (Ed.IPEC Japan) may be appropriately selected according to the need.

Examples of the dosage form include oral administration formulations(examples: tablets, capsules, granules, powders, oral liquids, syrups,oral jelly formulations and the like), oral cavity formulations(examples: tablets for the oral cavity, spray formulations for the oralcavity, semi-solid formulations for the oral cavity, oral rinse and thelike), formulations for injection (examples: injections and the like),formulations for dialysis (examples: agents for dialysis and the like),formulations for inhalation (examples: agents for inhalation and thelike), ophthalmic formulations (examples: ophthalmic solutions,ophthalmic ointments and the like), otological formulations (examples:ear drops and the like), nasologic formulations (examples: nasal dropsand the like), rectal formulations (examples: suppositories, semi-solidformulations for rectal administration, enema formulations and thelike), vaginal formulations (examples: vaginal tablets, vaginalsuppositories and the like), skin formulations (examples: topical solidformulations, topical liquids, spray formulations, ointments, creams,gels, plasters and pressure sensitive adhesives and the like) and thelike.

[Oral Administration Formulations]

Examples of an oral administration formulation include tablets,capsules, granules, powders, oral liquids, syrups, oral jellyformulations and the like. The oral administration formulation may beclassified into rapidly disintegrating formulations for which therelease of an active component from the formulations is not particularlycontrolled and release-controlled formulations for which the release iscontrolled according to the purposes by adjusting the dosage design andproduction method, such as enteric formulations and sustained releaseformulations. The enteric formulations refer to a formulation which isdesigned to release an active component mainly in the small intestinerather than in the stomach with the purpose of prevention ofdecomposition of the active component in the stomach or reduction ofstimulation of the stomach by the active component. The entericformulation may be generally produced by providing a coating of anacid-insoluble enteric base. The sustained release formulations refer toa formulation for which the release rate, release time and release siteof an active component from the formulation is controlled with thepurpose of reduction in the frequency of administration or reduction ofside effects. The sustained release formulation may be generallyproduced by using an appropriate agent for sustained release. Among theoral administration formulations, capsules, granules, tablets may beprovided with an appropriate coating film of a saccharide, sugaralcohol, polymer compound and the like with the purpose of easyingestion or prevention of decomposition of an active component.

(1) Tablets

Tablets are an orally administered solid formulation having a certainshape. Examples thereof include those generally referred to as tabletssuch as plain tablets, film-coated tablets, sugar-coated tablets,multilayered tablets and dry-coated tablets as well as orallydisintegrating tablets, chewable tablets, effervescent tablets,dispersible tablets, soluble tablets and the like. Plain tablets may begenerally produced according to the following procedure (a), (b) or (c):

(a) An active component is mixed with an additive such as a vehicle, abinding agent and a disintegrating agent to obtain a homogeneous mixturewhich is granulated by an appropriate method using water or a solutioncontaining a binding agent, mixed with a lubricant and the like,compressed and moulded;(b) An active component is mixed with an additive such as a vehicle, abinding agent and a disintegrating agent to obtain a homogeneous mixturewhich is then directly compressed and moulded, or granules prepared withan additive are mixed with an active component, a lubricant and the liketo obtain a homogeneous mixture which is then compressed and moulded;(c) An active component is mixed with an additive such as a vehicle anda binding agent to obtain a homogeneous mixture which is then wetted andkneaded with a solvent, moulded in a certain mould and dried by anappropriate method. Film-coated tablets may be generally produced byproviding appropriate thin coating films of a polymer and the like toplain tablets. Sugar-coated tablets may be generally produced byproviding coating films containing a saccharide or sugar alcohol toplain tablets. Multilayerd tablets may be produced by stacking layers ofpowder granules having different compositions and compressing andmoulding the product according to an appropriate method. Dry-coatedtablets may be produced by coating inner core tablets with outer layershaving different compositions. Tablets may be formed as enteric tabletsor sustained release tablets according to appropriate well-knownmethods. Orally disintegrating tablets, chewable tablets, effervescenttablets, dispersible tablets and soluble tablets are the tablets towhich unique functions are imparted by appropriately selectingadditives, and may be produced according to the production proceduresdescribed above for the tablets. Orally disintegrating tablets refer toa tablet ingested by rapid dissolution or disintegration in the oralcavity; chewable tablets refer to a tablet ingested by chewing;effervescent tablets refer to a tablet which is dissolved or dispersedin water with rapid effervescence; dispersible tablets refer to a tabletwhich is ingested after dispersion in water; and the soluble tabletsrefer to a tablet which is ingested after dissolution in water. Theeffervescent tablets may be produced by using an additive which is anappropriate acidic substance, carbonate salt, hydrogen carbonate saltand the like.

(2) Capsules

Capsules are a formulation containing a capsule shell filled with anactive component or an active component coated with a capsule base.Examples thereof include hard capsules, soft capsules and the like. Hardcapsules may be produced by mixing an active component with an additivesuch as a vehicle to obtain a homogeneous mixture, or obtaining granulesor moulded substance by an appropriate method, which is then directly,or after appropriately being moulded, added to a capsule shell. Softcapsules may be produced by capsulating and moulding a mixture of anactive component and an additive into a certain shape with anappropriate capsule base such as gelatine having an increased plasticityby addition of glycerol, D-sorbitol or the like. Capsules may be formedas enteric capsules or sustained release capsules according toappropriate well-known methods. An capsule base may be added with acolorant, a preservative or the like.

(3) Granules

Granules are a granulated formulation. Examples thereof include thosegenerally referred to as granules as well as effervescent granules.Granules may be generally produced according to the following procedure(a), (b) or (c):

(a) A powder active component is mixed with an additive such as avehicle, a binding agent or a disintegrating agent to obtain ahomogeneous mixture which is then granulated by an appropriate method;(b) A granulated active component is mixed with an additive such as avehicle to obtain a homogeneous mixture;(c) A granulated active component is mixed with an additive such as avehicle to obtain a homogeneous mixture which is then granulated by anappropriate method. Granules may be optionally provided with a film ormay be formed as enteric granules or sustained release granules usingappropriate well-known methods. Effervescent granules may be produced byusing an additive which is an appropriate acidic substance, carbonatesalt, hydrogen carbonate salt and the like. The effervescent granulesrefer to a granule which is dissolved or dispersed in water with rapideffervescence. The granules may also be formed as fine granules bycontrolling the particle size.

(4) Powders

Powders are powdery formulations and may be generally produced by mixingan active component with an additive such as a vehicle to obtain ahomogeneous mixture.

(5) Oral Liquids

Oral liquids are a formulation in the form of solution or flowable andviscous gel. Examples thereof include those generally referred to asoral liquids as well as elixirs, suspensions, emulsions, lemonades andthe like. Oral liquids may be generally produced by mixing an activecomponent with an additive and purified water to homogeneously dissolve,emulsify or suspend the active component and optionally filtering theproduct. Elixirs refer to a clear oral liquid containing ethanol havingsweet taste and aroma. Elixirs may be generally produced by dissolving asolid active component or an infusion thereof in ethanol, purifiedwater, a flavouring agent and sucrose, an additional saccharide or asweetening agent and obtaining a clear liquid by filtration or othermethods. Suspensions refer to an oral liquid in which an activecomponent is finely and homogeneously suspended. Suspensions may begenerally produced by suspending a solid active component in asuspending agent or an additional additive and purified water or oil andhomogenising the whole product according to an appropriate method.Emulsions refer to an oral liquid in which an active component is finelyand homogeneously emulsified. Emulsions may be generally produced byadding an emulsifying agent and purified water to a liquid activecomponent and emulsifying and homogenising the whole product accordingto an appropriate method. Lemonades refer to a clear oral liquid havingsweet taste and sour taste.

(6) Syrups

Syrups are a viscous liquid or solid formulation containing a saccharideor a sweetening agent. Examples thereof include agents for syrups.Syrups may be generally produced by dissolving, mixing, suspending oremulsifying an active component in a solution of sucrose, othersaccharides or a sweetening agent or solely a syrup and optionallyboiling the product followed by filtering while heating. Formulationsfor syrups refer to a granular or powdery formulation to which water isadded to provide syrups and may be sometimes referred to as dry syrups.Formulations for syrups may be generally produced according to theproduction procedures described above for the granules or powders byusing a saccharide or a sweetening agent as an additive.

(7) Oral Jelly Formulations

Oral jelly formulations are a shaped gel formulation withoutflowability. Oral jelly formulations may be generally produced by mixingan active component with an additive and a polymer gel base, allowingformation of gel and shaping into a certain shape according toappropriate methods.

[Oral Cavity Formulations] (1) Tablets for the Oral Cavity

Tablets for the oral cavity are a formulation having a certain shapewhich is administered to the oral cavity. Examples thereof includetroches, sublingual tablets, buccal tablets, adhering tablets, chewinggum tablets and the like. Tablets for the oral cavity may be generallyproduced according to the production procedures described for thetablets.

Troches refer to a tablet for the oral cavity which is graduallydissolved or disintegrated in the oral cavity and is applied locally tothe oral cavity or pharynx; sublingual tablets refer to a tablet for theoral cavity to be rapidly dissolved under the tongue to allow absorptionof an active component through oral mucosa; buccal tablets refer to atablet for the oral cavity to be gradually dissolved between the molarsand cheeks to allow absorption of an active component through oralmucosa; adhering tablets refer to a tablet for the oral cavity which isadhered to oral mucosa; and chewing gum tablets refer to a tablet forthe oral cavity to be chewed to release an active component.

(2) Spray Formulations for the Oral Cavity

Spray formulations for the oral cavity are a formulation to spray anactive component in the form of mist, powder, foam or paste. Sprayformulations for the oral cavity may be generally produced by dissolvingor suspending an active component and an additive in a solvent or thelike, optionally filtering thereof and packing the product into acontainer together with liquefied gas or compressed gas, or by preparinga solution or suspension with an active component and an additive andpacking the product into a container to which a spraying pump isattached.

(3) Semi-Solid Formulations for the Oral Cavity

Semi-solid formulations for the oral cavity are a formulation to beapplied to the oral mucosa. Examples thereof include creams, gels,ointments and the like. Semi-solid formulations for the oral cavity maybe generally produced by emulsifying an active component together withan additive in purified water and an oil component such as petrolatum,or by mixing an active component and an additive with a base such as apolymer gel or an oil or fat and obtaining a homogeneous mixture. Creamsrefer to a semi-solid formulation in the form of an oil-in-water orwater-in-oil emulsion and lipophilic formulations in the form of awater-in-oil emulsion may also be referred to as oil-based creams.Creams may be generally produced by preparing an oil phase frompetrolatum or a higher alcohol or a mixture thereof with an additivesuch as an emulsifying agent, separately preparing a water phase frompurified water or a mixture thereof with an additive such as anemulsifying agent, adding an active component either to the oil phase orthe water phase, heating both phases and mixing the oil phase and thewater phase until homogeneity to obtain an emulsion. Gels refer to a gelformulation and examples thereof include water-based gels, oil-basedgels and the like. Water-based gels may be produced by dissolving orsuspending an active component in an additive such as a polymer compoundand purified water and allowing crosslinking by heating and cooling oraddition of a gel-forming agent. Oil-based gels may be produced bymixing an active component with a liquid oil base such as a glycol or ahigher alcohol and an additive. Ointments refer to a semi-solidformulation containing an active component dissolved or dispersed in abase. Examples thereof include oil- or fat-based ointments,water-soluble ointments and the like. Oil- or fat-based ointments may begenerally produced by melting an oil- or fat-based base such as an oilor fat, a wax and a hydrocarbon including paraffin by heating,dissolving or dispersing an active component therein and mixing andkneading to obtain a homogeneous mixture. Water-soluble ointments may begenerally produced by melting a water-soluble base such as macrogol byheating and mixing and kneading an active component therein to obtain ahomogeneous mixture.

(4) Oral Rinses

Oral rinses are a liquid formulation to be applied locally to the oralcavity or pharynx and may include solid formulations which are dissolvedupon use. Oral rinses may be generally produced by homogeneouslydissolving an active component in a solvent and an additive andoptionally filtering the solution. Solid formulations which aredissolved upon use may be generally produced according to the productionprocedures described for the tablets and granules.

[Formulations for Injection] (1) Injections

Injections are an aseptic formulation in the form of solution,suspension or emulsion or solid to be dissolved or suspended upon use,which are directly administered to body tissues and organs such as underthe skin, in the muscle or to a vessel. Examples thereof include thosegenerally referred to as injections as well as lyophilised injections,powder injections, pre-filled syringes, cartridges, transfusions,implantable injections, sustained release injections and the like.Injections may be generally produced according to the followingprocedure (a) or (b):

(a) An active component or a mixture of an active component with anadditive is dissolved, suspended or emulsified in water for injection oranother aqueous solvent or a non-aqueous solvent and the product ispacked into a container for injection which is then sterilised;(b) An active component or a mixture of an active component with anadditive is dissolved, suspended or emulsified in water for injection oranother aqueous solvent or a non-aqueous solvent and the product issubjected to aseptic filtration or the product is homogeneously preparedin an aseptic manner and is charged into a container for injection whichis then sealed. Lyophilised injections may be generally produced bydissolving an active component or an active component together with anadditive such as a vehicle in water for injection, subjecting thesolution to aseptic filtration, charging the solution in a container forinjection followed by lyophilisation or lyophilising the solution in acontainer dedicated for lyophilisation followed by packing the productin a container for injection. Powder injections may be generallyproduced by aseptic filtration and crystallization to obtain powderwhich is directly or a mixture thereof with a sterilized additive ischarged into a container for injection. Pre-filled syringes may begenerally produced by charging an active component or a solution,suspension or emulsion of an active component and an additive into asyringe. Cartridges refer to an injection in the form of a cartridgecontaining a drug solution to be placed in a dedicated syringe.Cartridges containing a drug solution may be generally produced bycharging an active component or a solution, suspension or emulsion of anactive component and an additive into a cartridge. Transfusions refer toan injection generally of 100 mL or more which is intravenouslyadministered. Implantable injections refer to an injection in the formof a solid or gel, which is to be applied using an implantable tool orby surgery under the skin or in the muscle in order to release an activecomponent over a long period of time. Implantable injections may begenerally produced by forming a pellet, microsphere or gel with abiodegradable polymer compound. Sustained release injections refer to aninjection applied in the muscle in order to release an active componentover a long period of time and may be generally produced by dissolvingor suspending an active component in a vegetable oil or obtaining amicrosphere suspension with a biodegradable polymer compound.

[Formulations for Dialysis] (1) Agents for Dialysis

Agents for dialysis are a liquid formulation or a solid formulationdissolved upon use to be used for peritoneal dialysis or haemodialysis.Examples thereof include agents for peritoneal dialysis, agents forhaemodialysis and the like. Agents for peritoneal dialysis refer to anaseptic agent for dialysis used for peritoneal dialysis and may begenerally produced by charging a solution of an active component and anadditive in a solvent at a certain volume or a mixture of an activecomponent and an additive into a container, sealing the same andoptionally sterilizing the same. Solid formulations to be dissolved uponuse may be generally produced according to the production proceduresdescribed above for the tablets and granules. Agents for haemodialysisrefer to an agent for dialysis used for haemodialysis and may begenerally produced by charging a solution of an active component and anadditive in a solvent at a certain volume or a mixture of an activecomponent and an additive into a container. Solid formulations to bedissolved upon use may be generally produced according to the productionprocedures described above for the tablets and granules.

[Formulations for Inhalation] (1) Agents for Inhalation

Agents for inhalation are a formulation applied to the bronchus or lungby inhaling aerosols of an active component. Examples thereof includepowder agents for inhalation, liquid agents for inhalation, aerosols forinhalation and the like. Powder agents for inhalation refer to aformulation to be inhaled as aerosols of solid particles at apredetermined amount, and may be generally produced by preparing fineparticles of an active component and optionally mixing thereof with anadditive such as lactose to obtain a homogeneous mixture. Liquid agentsfor inhalation refer to a liquid agent for inhalation to be applied by anebuliser and the like and may be generally produced by homogeneouslydissolving or suspending an active component in a solvent, anappropriate tonicity agent, a pH-controlling agent and the like andoptionally filtering the product. Aerosols for inhalation refer to ametered-dose agent for inhalation to spray a predetermined amount ofactive component packed in a container together with a propellant.Aerosols for inhalation may be generally produced by preparing asolution or suspension from an active component, a solvent, anappropriate dispersant, a stabilising agent and the like and chargingthe product in a pressure resistant container attached with a flowregulating valve together with a liquid propellant.

[Ophthalmic Formulations] (1) Ophthalmic Solutions

Ophthalmic solutions are a liquid aseptic formulation or a solid asepticformulation to be dissolved or suspended upon use, which is applied toophthalmic tissue such as conjunctival sac. Ophthalmic solutions may begenerally produced by charging a solution or suspension of an activecomponent and an additive in a solvent or the like at a certain volumeor a mixture of an active component and an additive in a container.

(2) Ophthalmic Ointments

Ophthalmic ointments are a semi-solid aseptic formulation to be appliedto ophthalmic tissue such as conjunctival sac, and may be generallyproduced by charging a homogeneous mixture of a base such as petrolatumand a solution or fine powder of an active component in a container.

[Otological Formulations] (1) Ear Drops

Ear drops are a liquid or semi-solid formulation or a solid formulationto be dissolved or suspended upon use, which is administered to theexternal ear or middle ear. Ear drops are generally produced by charginga solution or suspension of an active component and an additive in asolvent or like at a certain volume or a mixture of an active componentand an additive in a container.

[Nasologic Formulations] (1) Nasal Drops

Nasal drops are a formulation to be administered to the nasal cavity ornasal mucosa and examples thereof include nasal powders, nasal liquidsand the like. Nasal powders refer to a fine powder nasal drop to beadministered to the nasal cavity and may be generally produced by makingappropriately fine powder of an active component and optionally mixingthe active component with an additive to obtain a homogeneous mixture.Nasal liquids refer to a nasal drop which is liquid or solid to bedissolved or suspended upon use and is administered to the nasal cavity.Nasal liquids may be generally produced by dissolving or suspending anactive component in a solvent and an additive and optionally filteringthe product. An additive for nasal liquids which may be used includes atonicity agent, a pH controlling agent and the like.

[Rectal Formulations] (1) Suppositories

Suppositories are a semi-solid formulation having a certain shape, whichis applied in the rectum and releases an active component by melting atbody temperature or gradually dissolving or dispersing in water.Suppositories may be generally produced by dissolving or homogeneouslydispersing a homogeneous mixture of an active component with an additivesuch as a dispersant and an emulsifying agent in a base liquefied byheating and the like, charging a predetermined amount of the product ina container and solidifying/moulding the same. A base for suppositorieswhich may be generally used includes oil- or fat-based bases andhydrophilic bases.

(2) Semi-Solid Formulations for Rectal Administration

Semi-solid formulations for rectal administration are a formulationapplied around or in the anus and examples thereof include rectalcreams, rectal gels, rectal ointments and the like. Semi-solidformulations for rectal administration may be generally produced byemulsifying an active component together with an additive in purifiedwater and an oil component such as petrolatum, or by homogeneouslymixing an active component and an additive with a base which is apolymer gel or an oil or fat. Rectal creams may be generally produced bypreparing an oil phase from petrolatum or a higher alcohol or a mixturethereof with an additive such as an emulsifying agent, separatelypreparing a water phase from purified water or a mixture thereof with anadditive such as an emulsifying agent, adding an active component eitherto the oil phase or the water phase, heating both phases and mixing theoil phase and the water phase until homogeneity to obtain an emulsion.Rectal gels refer to a gel formulation and examples thereof includewater-based gels, oil-based gels and the like. Water-based gels may beproduced by dissolving or suspending an active component in an additivesuch as a polymer compound and purified water and allowing crosslinkingby heating and cooling or addition of a gel-forming agent. Oil-basedgels may be produced by mixing an active component with a liquid oilbase such as a glycol or a higher alcohol and an additive. Rectalointments refer to a semi-solid formulation containing an activecomponent dissolved or suspended in a base and examples thereof includeoil- or fat-based ointments, water-soluble ointments and the like. Oil-or fat-based ointments may be generally produced by melting an oil- orfat-based base such as an oil or fat, a wax and a hydrocarbon includingparaffin by heating, dissolving or suspending an active componenttherein and mixing and kneading to obtain a homogeneous mixture.Water-soluble ointments may be generally produced by melting awater-soluble base such as macrogol by heating and mixing and kneadingan active component therein to obtain a homogeneous mixture.

(3) Enema Formulations

Enema formulations are a liquid or viscous gel formulation to be appliedthrough the anus. Enema formulations are generally produced bydissolving or suspending an active component in a solvent or the like ata certain volume using purified water or an appropriate aqueous solventand charging the product in a container. An additive which may be usedfor enema formulations includes a dispersant, a stabilising agent, a pHcontrolling agent and the like.

[Vaginal Formulations] (1) Vaginal Tablets

Vaginal tablets are a solid formulation having a certain shape, which isapplied in the vagina and releases an active component by graduallydissolving or dispersing in water. Vaginal tablets may be generallyproduced according to the production procedures described above for thetablets.

(2) Vaginal Suppositories

Vaginal suppositories are a semi-solid formulation having a certainshape, which is applied in the vagina and releases an active componentby melting at body temperature or gradually dissolving or dispersing inwater. Vaginal suppositories may be generally produced according to theproduction procedures described above for the rectal suppositories andthe like.

[Skin Formulations] (1) Topical Solid Formulations

Topical solid formulations are a solid formulation to be applied orspread on skin including the scalp or nails and examples thereof includetopical powders. Topical powders refer to a topical solid powderformulation and may be generally produced by mixing an active componentwith an additive such as a vehicle to obtain a homogeneous mixture whichis then formed into powders.

(2) Topical Liquids

Topical liquids are a liquid formulation to be applied on skin includingthe scalp or nails and examples thereof include liniments, lotions andthe like. Topical liquids may be generally produced by dissolving,emulsifying or suspending an active component in a solvent, an additiveand the like and optionally filtering the product. Liniments refer to aliquid or muddy topical liquid to be rubbed into the skin. Lotions referto a topical liquid containing an active component dissolved, emulsifiedor finely dispersed in an aqueous liquid. Lotions may be generallyproduced by preparing a solution, suspension or emulsion of an activecomponent, an additive and purified water to obtain a homogeneousproduct.

(3) Spray Formulations

Spray formulations are a formulation to spray an active component in theform of mist, powder, foam or paste on the skin and examples thereofinclude topical aerosols, pump spray formulations and the like. Sprayformulations may be generally produced by preparing a solution orsuspension of an active component, optionally filtering the product andcharging the product in a container. Topical aerosols refer to a sprayformulation which sprays an active component together with liquefied gasor compressed gas packed in a container. Topical aerosols may begenerally produced by preparing a solution or suspension of an activecomponent and packing the product into a pressure resistant containerattached with a continuous injection valve together with a liquidpropellant. An additive such as a dispersant and a stabilising agent maybe optionally added to topical aerosols. Pump spray formulations referto a spray formulation which sprays an active component in a containerby means of a pump. Pump spray formulations may be generally produced bydissolving or suspending an active component and an additive andcharging the product in a container to which a pump is attached.

(4) Ointments

Ointments are a semi-solid formulation to be applied on the skincontaining an active component dissolved or dispersed in a base.Examples thereof include oil- or fat-based ointments, water solubleointments and the like. Oil- or fat-based ointments may be generallyproduced by melting an oil- or fat-based base such as an oil or fat, awax and a hydrocarbon including paraffin by heating, dissolving orsuspending an active component therein and mixing and kneading to obtaina homogeneous mixture. Water soluble ointments may be generally producedby melting a water-soluble base such as macrogol by heating and mixingand kneading an active component therein to obtain a homogeneousmixture.

(5) Creams

Creams are a semi-solid formulation in the form of an oil-in-water orwater-in-oil emulsion to be applied on the skin and lipophilicformulations in the form of a water-in-oil emulsion may also be referredto as oil-based creams. Creams may be generally produced by preparing anoil phase from petrolatum or a higher alcohol or a mixture thereof withan additive such as an emulsifying agent, separately preparing a waterphase from purified water or a mixture thereof with an additive such asan emulsifying agent, adding an active component either to the oil phaseor the water phase, heating both phases and mixing the oil phase and thewater phase until homogeneity to obtain an emulsion.

(6) Gels

Gels are a gel formulation to be applied on the skin and examplesthereof include water-based gels and oil-based gels. Water-based gelsmay be generally produced by dissolving or suspending an activecomponent in an additive such as a polymer compound and purified waterand allowing crosslinking by heating and cooling or addition of agel-forming agent. Oil-based gels may be produced by mixing an activecomponent with a liquid oil base such as a glycol or a higher alcoholand an additive.

(7) Plasters and Pressure Sensitive Adhesives

Plasters and pressure sensitive adhesives are a formulation to beadhered on the skin and examples thereof include tapes and cataplasms.Plasters and pressure sensitive adhesives may be generally produced byhomogeneously mixing an active component with a base which is a polymercompound or a mixture thereof, spreading the mixture on a support or aliner (release material) and shaping the same. Plasters and pressuresensitive adhesives may be formed as transdermal absorption formulationsby using a release-controlled film. An additive such as an adhesive oran absorption-promoting agent may be optionally used for plasters andpressure sensitive adhesives. Tapes refer to a plaster and pressuresensitive adhesive containing a base that contains little water andexamples thereof include plasters and the like. Tapes may be generallyproduced with a base which is a water insoluble natural or syntheticpolymer compound such as a resin, a plastic, a rubber or the like byspreading on a fabric or spreading on or incorporating into a plasticfilm an active component or a homogeneous mixture of an active componentand an additive and shaping the product. Tapes may also be produced byincorporating a mixture of an active component and a base or anotheradditive into a release material made of a release-controlled film, asupport and a liner (release material) and shaping the same. Cataplasmsrefer to a plaster and pressure sensitive adhesive containing a basewhich contains water and may be generally produced by homogeneouslymixing an active component with a liquid substance such as purifiedwater or glycerol or homogeneously mixing and kneading a natural orsynthetic polymer compound such as a water soluble polymer or awater-absorbable polymer and purified water together with an activecomponent, spreading the mixture on a fabric or the like and shaping thesame.

Unless otherwise defined, all technical and scientific terms andabbreviations used herein have the same meanings as those commonlyunderstood by a person skilled in the art to which the present inventionbelongs.

Contents of all patent literatures and non patent literatures orreferences explicitly cited herein may be incorporated herein as a partof the present specification.

EXAMPLES

The present invention is hereinafter specifically described by way ofExamples and Biological Examples which do not limit the presentinvention. The present compounds and compounds described in Examples aredenominated according to the IUPAC nomenclature. Naming according to theIUPAC nomenclature can be done using, for example, ACD/Name (version2019.2.0, available from Advanced Chemistry Development Inc.), ACD/NameBatch (version 12.02.45356, available from Advanced ChemistryDevelopment Inc.) or ChemDraw Professional (version 17.1.0.105 or18.0.0.231, available from PerkinElmer Inc.) In each of the followingExamples, the name of the objective compound of the Example is describedsubsequently to the number of the Example, and the compound is sometimesreferred to as the “title compound”.

Analytical Methods

¹H NMR spectra were recorded on Bruker DRX-400 instruments and arecalibrated using residual undeuterated solvent (CHCl₃, DMSO, MeOH at7.26, 2.50 and 3.31 ppm for ¹H NMR, respectively). Chemical shifts (δ)are quoted in parts per million (ppm) and referenced to the appropriateNMR solvent peak(s) and are assigned in accordance with numbereddiagrams; with resonances described as s (singlets), d (doublets), t(triplets), q (quartets), combinations thereof (i.e. td indicates atriplet of doublets) or m (multiplets) and br s (broad singlet).

The Liquid Chromatography Mass Spectroscopy (LCMS) systems used are:

General LCMS Procedures Method 1

Simadzu LC20-MS2010, Agilent Pursit 5 C₁₈ 20×2.0 mm at 50° C. Elutionwith A: 1.5 mL of TFA in 4 L water; B: 0.75 mL of TFA in acetonitrile.Gradient:

Gradient-Time flow mL/min % A % B 0.00 1.5 95  5 0.70 1.5  5 95 1.10 1.5 5 95 1.11 1.5 95  5 1.50 1.5 95  5Detection—MS, UV 220, 254 nm. MS ionization method—Electrospray(positive ion).

Method 2:

Simadzu LC20-MS2010, Xbridge Shield RP-18.5 um, 2.1×50 mm at 50° C.Elution with A: 0.8 mL of NH₃—H₂O in 4 L water; B: acetonitrile.Gradient:

Gradient-Time flow mL/min % A % B 0.00 1.0 50  50 2.00 1.0  0 100 2.481.0  0 100 2.49 1.0  5  50 3.00 1.0 50  50Detection—MS, UV 220, 254 nm. MS ionization method—Electrospray(positive ion). Column: XBridge C18 3.5 um 2.1×50 mm;The High Performance Liquid Chromatography (HPLC) systems used are:

General HPLC Procedures Method 1

SHIMADZU 20A, Ultimate C₁₈ 3.0×50 mm, 3 um at 40° C. Elution with A:2.75 mL of TFA in 4 L water; B: 2.5 mL of TFA in acetonitrile. Gradient:

Gradient-Time flow mL/min % A % B  0.00 1.2 70 30  6.00 1.2 10 90  8.001.2 10 90  8.01 1.2 70 30 10.00 1.2 70 30Detection—MS, UV 220, 254 nm. MS ionization method—Electrospray(positive ion).

Method 2

SHIMADZU 20A, Ultimate C₁₈ 3.0×50 mm, 3 um at 40° C. Elution with A:2.75 mL of TFA in 4 L water; B: 2.5 mL of TFA in acetonitrile. Gradient:

Gradient-Time flow mL/min % A % B  0.00 1.2 90 10  6.00 1.2 20 80  8.001.2 20 80  8.01 1.2 90 10 10.00 1.2 90 10Detection—MS, UV 220, 254 nm. MS ionization method—Electrospray(positive ion).

Method 3:

SHIMADZU LC20-MS2020, Xbridge Shield RP-18, 5 um, 2.1×50 mm at 50° C.Elution with A: 0.8 mL of NH₃.H₂O in 4 L water; B: acetonitrile.Gradient:

Gradient-Time flow mL/min % A % B 0.00 0.8 90 10 6.00 0.8 20 80 6.50 0.820 80 6.51 0.8 90 10 7.00 0.8 90 10Detection—MS, UV 220, 254 nm. MS ionization method—Electrospray(positive ion).The chiral Supercritical Fluid Chromatography (SFC) systems used are:

Chiral SFC Procedures Method 1: Column: ChiralPak AD-3 150×4.6 mm I.D.,3 um

Mobile phase: A: CO₂ B:IPA (0.05% DEA)

Isocratic: 40% B

Flow rate: 2.5 mL/min Column temp.:40° C.Back pressure: 100 bar

Method 2: Column: Chiralcel OJ-3 150×4.6 mm I.D., 3 um

Mobile phase: A: CO₂ B: EtOH (0.05% DEA)Gradient: from 5% to 40% of B in 5 min and from 40% to 5% of B in 0.5min, hold 5% of B for 1.5 minFlow rate: 2.5 mL/minColumn temp.: 35° C.

ABPR: 1500 psi Method 3: Column: Chiralcel OD-3 150×4.6 mm I.D., 3 um

Mobile phase: A: CO₂ B: EtOH (0.05% DEA)Gradient: from 5% to 40% of B in 5 min and from 40% to 5% of B in 0.5min, hold 5% of B for 1.5 minFlow rate: 2.5 mL/minColumn temp.: 35° C.

ABPR: 1500 psi Abbreviations

2-MeTHF=2-methyl tetrahydrofuran;4A MS=molecular sieves, 4A;DAST=N,N-diethylaminosulfur trifluorid;DCM=dichloromethane;DE=diethyl ether;DEA=diethylamine;DIPEA=diisopropyl ethylamine;

DMF=N,N-dimethylformamide;

DMP=Dess-Martin periodinane;DMSO=dimethyl sulfoxide;dppf=1,1′-Ferrocenebis(diphenylphosphine);EA=ethyl acetate;EDCI=1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide;HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate;MTBE=methyl tert-butyl ether;

NBS=N-bromosuccinimide; NCS=N-chlorosuccinimide;

PE=petroleum ether;TBHP=tert-butyl hydroperoxide;TEA=triethylamine;TFA=trifluoroacetic acid;THF=tetrahydrofuran;TLC=thin layer chromatography; andX-Phos=2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

Example 1[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone

tert-butyl(1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (PharmablockInc., catalog No. PBG0012)(2 g, 9.47 mmol) in EtOH (20 mL) were addedAcOH (0.54 mL, 9.47 mmol, 1.0 eq.), KOAc (0.93 g, 9.47 mmol, 1.0 eq.).Then NH₂OH.HCl (0.47 mL, 11.36 mmol) was added to the mixture. Themixture was stirred at 25° C. for 2 h to give white suspension. Thereaction mixture was poured into H₂O (40 mL) and extracted with EtOAc(40 mL×3). The combined organic layers were washed with brine (60 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the title compound as white solid.

TLC: Rf=0.4, PE:EtOAc=3:1;

LC-MS Method1 0.694 min, MS (m/z) 170.8 (M−tBu, +H⁺);¹H NMR (400 MHz, CHLOROFORM-d) δ=7.16 (d, J=7.6 Hz, 0.5H), 6.13 (d,J=8.8 Hz, 0.5H), 3.75-3.55 (m, 2H), 3.50-3.35 (m, 2H), 2.23-2.15 (m,0.5H), 2.10 (s, 1.5H), 1.80 (brs, 1H), 1.44 (s, 9H).

tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(2.2 g, 9.72 mmol) in DMF (18.4 mL) were added N-chlorosuccinimide (1363mg, 10.21 mmol), the mixture was stirred at 20° C. for 2 h. The mixturewas poured into H₂O (90 mL), extracted by EtOAc (50 mL×3). The organicphase was washed with brine (50 mL×3), dried over anhydrous Na₂SO₄,concentrated to give the title compound as a white solid.

LC-MS Method1 0.780 min, MS (m/z) 245.9 (M+H⁺).

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.42 (s, 1H), 3.75 (d, J=11.2 Hz,1H), 3.64 (d, J=10.8 Hz, 1H), 3.38 (d, J=10.8 Hz, 2H), 2.06 (s, 2H),1.76 (t, J=3.2 Hz, 1H), 1.45 (s, 9H). tert-butyl(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.38 mmol) and Et₃N (0.19 mL, 1.15 mmol) in DMF (1.0 mL) wasadded 2-methylprop-1-ene (0.72 mL, 1.15 mmol) (15% in isopropyl ether),and the mixture was stirred at 20° C. for 16 h. The reaction mixture waspoured into H₂O (20 mL), extracted with EtOAc (20 mL×3). The organicphase was washed with brine (20 mL×3), dried over anhydrous Na₂SO₄,concentrated to give the title compound (100 mg, 0.356 mmol, 92.9%yield) as a yellow oil.

LC-MS Method1 0.852 min, MS (m/z): 281 (M+H⁺).

¹H NMR (400 MHz, DIMETHYL SUlFOXIDE-d6) δ ppm 3.50 (d, J=11.1 Hz, 2H),3.30 (d, J=10.8 Hz, 2H), 2.61 (s, 2H), 1.91 (t, J=2.7 Hz, 2H), 1.40-1.38(m, 1H), 1.37 (s, 9H), 1.23 (s, 6H).(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride

The mixture of tert-butyl(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.36 mmol) in HCl/Dioxane (2.0 mL, 8.0 mmol, 4.0 M) was stirredat 20° C. for 0.5 h. The mixture was concentrated to afford the titlecompound (100 mg, 0.46 mmol, 129% yield, crude) as a yellow oil.

LC-MS Method1 0.232 min, MS (m/z): 181 (M−HCl+H⁺).¹H NMR (400 MHz, DIMETHYL SUIFOXIDE-d6) δ ppm 9.53 (brs, 1H), 9.06 (brs,1H), 3.40-3.26 (m, 4H), 2.60 (s, 2H), 2.12 (brs, 2H), 1.99 (m, 1H), 1.23(s, 6H).

[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone

To a solution of(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (100 mg, 0.46 mmol), 1-isopropylimidazole-4-carboxylicacid (92 mg, 0.6 mmol) and DIPEA (0.38 mL, 2.31 mmol) in DMF (3.0 mL)was added HATU (194 mg, 0.51 mmol), and the mixture was stirred at 20°C. for 16 h. The mixture was poured into H₂O (30 mL), extracted byEtOAc. The organic phase was washed with brine, dried over anhydrousNa₂SO₄, concentrated to give a residue. The residue was purified byPrep-HPLC (NH₃) to afford the title compound (4 mg, 0.012 mmol, 2.7%yield) as a white solid.

¹H NMR (400 MHz, CDCl₃-d): δ ppm 1.38 (s, 6H) 1.46 (t, J=3.5 Hz, 1H)1.51 (d, J=6.8 Hz, 6H) 1.98 (br d, J=3.5 Hz, 1H) 2.08 (br d, J=3.0 Hz,1H) 2.64 (s, 2H) 3.62 (dd, J=12.5, 4.5 Hz, 1H) 3.95 (dd, J=11.9, 3.6 Hz,1H) 4.20 (d, J=12.5 Hz, 1H) 4.36 (dt, J=13.5, 6.7 Hz, 1H) 4.75 (d,J=12.0 Hz, 1H) 7.47 (d, J=1.3 Hz, 1H) 7.67 (d, J=1.5 Hz, 1H)LCMS Method 1 0.65 mins MS (m/z) 317.0 [M+H⁺]

Example 2[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-methyl-1H-imidazol-4-yl)methanone[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-methyl-1H-imidazol-4-yl)methanone

To a mixture of 1-methyl-1H-imidazole-4-carboxylic acid (52.47 mg, 0.42mmol), EDCI (79.76 mg, 0.42 mmol) in Pyridine (1.0 mL) was added(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (91 mg, 0.42 mmol). The suspension was stirred at 20° C.for 8 hr. The reaction mixture was concentrated in vacuum. The residuewas purified by prep-HPLC (NH₃) and lyophilized to afford the titlecompound (17.45 mg, 21.8% yield) as yellow solid.

LC-MS Method1: 0.691 min, MS (m/z): 289.2 (M+H⁺).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.56 (d, J=1.25 Hz, 1H), 7.38 (s,1H), 4.70 (d, J=12.05 Hz, 1H), 4.19 (d, J=12.30 Hz, 1H), 3.94 (dd,J=12.05, 4.02 Hz, 1H), 3.72 (s, 3H), 3.61 (dd, J=12.55, 4.27 Hz, 1H),2.64 (s, 2H), 2.05-2.11 (m, 1H), 1.95-2.01 (m, 1H), 1.46 (t, J=3.39 Hz,1H), 1.38 (s, 6H)

Example 3[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-ethyl-1H-imidazol-4-yl)methanoneethyl 1-ethyl-1H-imidazole-4-carboxylate

A mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate andethylamine (1608.2 mg, 35.67 mmol, 1.60 mL, 20 eq) was stirred at 40° C.for 16 hr. The solution was then concentrated in vacuum. The residue waspurified by prep-TLC (PE:EtOAc=0:1, Rf=0.2) to afford the title compound(126 mg, crude) as yellow oil.

LC-MS Method1: 0.259 min, MS (m/z): 168.8 (M+H⁺).

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.64 (s, 1H), 7.51 (s, 1H), 4.37(q, J=7.2 Hz, 2H), 4.04 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.26(t, J=7.2 Hz, 3H). 1-ethyl-1H-imidazole-4-carboxylic acid

To a mixture of ethyl 1-ethyl-1H-imidazole-4-carboxylate in H₂O (0.5 mL)and THF (1.5 mL) was added LiOH.H₂O (47.16 mg, 1.12 mmol, 1.5 eq). Thesuspension was stirred at 40° C. for 6 hr. The residue was diluted withH₂O (1 mL), extracted with EtOAc (5 mL×4). The afforded H₂O layer wasbasified with 1 N HCl aq. to pH=5, The combined organic layers wereconcentrated and then lyophilized to afford the title compound (70 mg,crude) as yellow solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.69 (s, 1H), 7.45 (s, 1H), 3.98(q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-ethyl-1H-imidazol-4-yl)methanone

To a mixture of 1-ethyl-1H-imidazole-4-carboxylic acid in Pyridine (1mL) were added EDCI (95.54 mg, 0.50 mmol) and(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (72 mg, 0.33 mmol). The suspension was stirred at 20° C.for 16 hr. The solution was purified by Prep-HPLC (NH₃) and lyophilizedto afford the title compound (23.69 mg, 23.58% yield) as yellow solid.

LC-MS Method1: 2.045 min, MS (m/z): 303.2 (M+H⁺).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.54 (d, J=1.25 Hz, 1H) 7.35 (d,J=1.25 Hz, 1H) 4.65 (d, J=12.05 Hz, 1H) 4.12 (d, J=12.30 Hz, 1H) 3.94(q, J=7.28 Hz, 2H) 3.87 (dd, J=12.05, 4.02 Hz, 1H) 3.54 (dd, J=12.55,4.27 Hz, 1H) 2.57 (s, 2H) 2.00 (dt, J=7.47, 3.92 Hz, 1H) 1.91 (br d,J=3.76 Hz, 1H) 1.37-1.44 (m, 4H) 1.30 (s, 7H)

Example 4(1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonemethyl 1-cyclopropyl-1H-imidazole-4-carboxylate

To a suspension of 2,2′-bipyridine (618.79 mg, 3.96 mmol), Cu(OAc)₂(720.01 mg, 3.96 mmol), Na₂CO₃ (840.54 mg, 7.93 mmol) in DCE (30 mL)were added methyl 1H-imidazole-4-carboxylate (500 mg, 3.96 mmol) andcyclopropylboronic acid (681.15 mg, 7.93 mmol). The mixture was stirredat 70° C. for 16 h under O₂. TLC (PE:EtOAc=1:4) showed the reaction wascompleted. The reaction mixture was cooled to 23° C. The solid wasremoved by filtration and the filtrate was concentrated under vacuum.The residue was purified by flash column (PE to 20% EtOAc in PE). Thecombined organic layers were concentrated under reduced pressure toafford the title compound (140 mg, 0.8425 mmol, 21.249% yield) as abrown oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.66 (s, 1H), 7.60 (s, 1H), 3.87(s, 3H), 3.42-3.36 (m, 1H), 1.10-0.90 (m, 4H).1-cyclopropyl-1H-imidazole-4-carboxylic acid

To a solution of methyl 1-cyclopropyl-1H-imidazole-4-carboxylate (140mg, 0.84 mmol) in THF (3 mL) and H₂O (1 mL) was added LiOH.H₂O (0.06 mL,1.1 mmol). The resulting mixture was stirred at 20-25° C. for 2 h togive white suspension. TLC (PE:EtOAc=1:4) showed the reaction wascompleted (Rf=0). The reaction mixture was concentrated directly. Theresidue was acidified with 1 M HCl aq. to pH=6, then the combinedorganic layers were lyophilized to afford the title compound (120 mg,0.7887 mmol, 93.618% yield) as a white solid.

(1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 1-cyclopropyl-1H-imidazole-4-carboxylic acid (120 mg,0.79 mmol) in DMF (3 mL) were added at HATU (361.82 mg, 0.95 mmol), Et₃N(0.51 mL, 3.94 mmol),(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (142.16 mg, 0.79 mmol). The resulting mixture was stirredat 20-25° C. for 14 hours. The residue was purified by prep-HPLC (HCl).The combined organic layers were concentrated and then lyophilized toafford the title compound (4.8 mg, 0.0137 mmol, 1.7347% yield) as alight yellow gum.

LC-MS Method1: 315.0 [M+H⁺]

¹H NMR (400 MHz, METHANOL-d₄) δ=8.68-8.33 (m, 1H), 7.91 (br s, 1H),4.10-3.84 (m, 3H), 3.60 (br d, J=4.8 Hz, 2H), 2.63 (s, 2H), 2.16-1.99(m, 2H), 1.44 (br s, 1H), 1.24 (s, 7H), 1.07 (d, J=6.5 Hz, 4H).

Example 5(1-cyclobutyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanoneethyl 1-cyclobutyl-1H-imidazole-4-carboxylate

A mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (400 mg,2.38 mmol) and cyclobutanamine (1.02 mL, 11.89 mmol) was heated at 50°C. for 16 hr. The mixture was concentrated in vacuum, then the residuewas purified by flash column (0-100% EA in PE, 0.5% NH₃—H₂O) to give thetitle compound (420 mg, 2.1624 mmol, 90.923% yield) as yellow oil.

LC-MS Method1 0.568 min, MS (M/Z) 194.9 (M+H⁺).

1-cyclobutyl-1H-imidazole-4-carboxylic acid

To a mixture of ethyl 1-cyclobutyl-1H-imidazole-4-carboxylate (100 mg,0.5100 mmol) in THF (0.8578 mL) and H₂O (1.0722 mL) was added LiOH.H₂O(0.09 mL, 1.54 mmol). The resulting suspension was then stirred at 20°C. for 3.5 hr. TLC (100% EA) showed new spot (Rf=0) and the reactant wasconsumed completely. The aqueous phase was washed with DCM (3 mL×2) andacidified with 1N HCl to pH=2. The residual aqueous solution waslyophilized to give the title compound (160 mg, 0.9628 mmol, 187.01%yield) as pale yellow solid.

¹H NMR (400 MHz, D₂O) δ ppm 8.77 (s, 1H), 8.03 (s, 1H), 4.85-4.75 (m,1H), 2.50-2.40 (m, 2H), 2.40-2.30 (m, 2H), 1.90-1.75 (m, 2H).

(1-cyclobutyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of 1-cyclobutyl-1H-imidazole-4-carboxylic acid (110 mg,0.5400 mmol) in DMF (0.9736 mL) were added HATU (247.8 mg, 0.6500 mmol),DIPEA (0.45 mL, 2.7 mmol) and(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (97.36 mg, 0.5400 mmol). The resulting mixture was stirredat 20° C. for 4 hr. The reaction mixture was diluted with H₂O (5 mL),extracted with EtOAc (5 mL×2). The combined organic layers wereseparated, then dried over Na₂SO₄ and concentrated in vacuum to givecrude oil. The crude oil was purified by prep-TLC (EA/MeOH=10/1), thenPrep-HPLC (NH₃) and lyophilized to give the title compound (12.15 mg,0.0370 mmol, 6.8494% yield) as pale yellow solid.

LC-MS Method1: 328.9

¹H NMR (400 MHz, DMSO-d₆) δ=8.03 (d, J=1.3 Hz, 1H), 7.99 (s, 1H),4.96-4.89 (m, 1H), 4.75 (br d, J=12.0 Hz, 1H), 4.12 (hr d, J=12.3 Hz,1H), 3.99 (br d, J=9.0 Hz, 1H), 3.66 (br s, 1H), 2.83 (s, 2H), 2.57 (t,J=8.7 Hz, 4H), 2.25 (br d, J=11.3 Hz, 1H), 2.17 (br s, 1H), 2.00-1.90(m, 2H), 1.60-1.57 (m, 1H), 1.44 (s, 6H)

Example 6[1-(bicyclo[1.1.1]pent-1-yl)-1H-imidazol-4-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanoneethyl 1-(bicyclo[1.1.1]pent-1-yl-1H-imidazole-4-carboxylate

To a mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (100 mg,0.5900 mmol) in 1-Butanol (0.40 mL) were addedbicyclo[1.1.1]pentan-1-amine (284.42 mg, 2.38 mmol) and Et₃N (0.58 mL,4.46 mmol). The resulting mixture was heated at 76° C. for 16 hr. Thereaction mixture was diluted with H₂O (5 mL) and extracted with EtOAc (5mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuum to give the title compound (100 mg, crudeproduct) as yellow oil.

1-(bicyclo[1.1.1]pent-1-yl)-1H-imidazole-4-carboxylic acid

To a mixture of ethyl1-(bicyclo[1.1.1]pent-1-yl)-1H-imidazole-4-carboxylate (100 mg, 0.4800mmol) in H₂O (1 mL) and MeOH (0.80 mL) was added LiOH.H₂O (0.06 mL,0.9700 mmol). The reaction was stirred at 25° C. for 16 hr. The aqueousphase was washed with DCM (3 mL×2) and acidified with 1N HCl to pH=2.The aqueous solution was lyophilized to give the title compound (50 mg,0.2806 mmol, crude product) as pale yellow solid.

[1-(bicyclo[1.1.1]pent-1-yl)-1H-imidazol-4-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of 1-(bicyclo[1.1.1]pent-1-yl)-1H-imidazole-4-carboxylicacid (59.54 mg, 0.2800 mmol) in DMF (0.50 mL) were added HATU (137.86mg, 0.3600 mmol), DIPEA (0.18 mL, 1.11 mmol) and(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (50 mg, 0.2800 mmol). The resulting mixture was stirred at20° C. for 4 hr. The reaction mixture was diluted with H₂O (5 mL) andextracted with EtOAc (5 mL×2), The combined organic layers wereseparated, washed with brine (8 mL), dried over Na₂SO₄ and concentratedin vacuum to give crude oil. The crude oil was purified by prep-HPLC(NH₃) to give the title compound (2.4 mg, 0.0071 mmol, 2.5416% yield) asyellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=7.76 (d, J=1.0 Hz, 1H), 7.71 (d, J=1.3 Hz,1H), 4.53 (br d, J=11.8 Hz, 1H), 3.93 (br d, J=12.0 Hz, 1H), 3.81 (brdd, J=3.6, 11.9 Hz, 1H), 3.47 (br dd, J=3.6, 11.9 Hz, 1H), 2.65 (s, 2H),2.24 (s, 6H), 2.08-1.93 (m, 3H), 1.40 (t, J=3.4 Hz, 1H), 1.26-1.25 (m,1H), 1.25 (s, 5H).

Example 7(1-cyclopentyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanoneethyl 1-cyclopentyl-1H-imidazole-4-carboxylate

A mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (200 mg,1.19 mmol) and cyclopentyl amine (0.58 mL, 5.95 mmol) was heated at 50°C. for 16 hr. The mixture was concentrated in vacuum. The residue waspurified by flash column (0-100% EA in PE, 0.5% NH₃H₂O) to give thetitle compound (240 mg, 1.1524 mmol, 96.912% yield) as yellow oil.

LC-MS Method1 0.668 min, MS (M/Z) 209.1 (M+H⁺).

1-cyclopentyl-1H-imidazole-4-carboxylic acid

To a mixture of ethyl 1-cyclopentyl-1H-imidazole-4-carboxylate (100 mg,0.4800 mmol) in THF (0.80 mL) and H₂O (1 mL) was added LiOH.H₂O (0.08mL, 1.44 mmol). The reaction mixture was stirred at 25° C. for 3.5 hr.The aqueous phase was washed with DCM (3 mL×2) and acidified with 1N HClto pH=2. The residual aqueous solution was lyophilized to give the titlecompound (150 mg, crude product) as pale yellow solid.

¹H NMR (400 MHz, D₂O) 8 ppm 8.73 (s, 1H), 7.90 (s, 1H), 4.75-4.70 (m,1H), 2.25-2.10 (m, 2H), 1.90-1.60 (m, 6H).

(1-cyclopentyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of 1-cyclopentyl-1H-imidazole-4-carboxylic acid (60.38 mg,0.2800 mmol) in DMF (0.50 mL) were added HATU (137.86 mg, 0.3600 mmol),DIPEA (0.18 mL, 1.11 mmol) and(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (50 mg, 0.2800 mmol). The resulting mixture was stirred at20° C. for 4 hr. The reaction mixture was diluted with H₂O (5 mL) andextracted with EtOAc (5 mL×2). The combined organic layers wereseparated, washed with brine (8 mL), dried over Na₂SO₄ and concentratedin vacuum to give crude oil. The crude oil was purified by prep-TLC(EA/MeOH=10/l), then prep-HPLC (NH₃) and lyophilized to give the titlecompound (11 mg, 0.0321 mmol, 4.6614% yield) as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ=7.78 (d, J=1.3 Hz, 1H), 7.73 (d, J=1.3 Hz,1H), 4.66-4.51 (m, 2H), 3.93 (br d, J=12.3 Hz, 1H), 3.81 (br d, J=6.5Hz, 1H), 3.47 (br d, J=11.8 Hz, 1H), 2.65 (s, 2H), 2.19-2.03 (m, 3H),1.99 (br d, J=6.0 Hz, 1H), 1.79 (br s, 4H), 1.64 (br s, 2H), 1.25 (s,7H)

Example 8(1-cyclohexyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanoneethyl 1-cyclohexyl-1H-imidazole-4-carboxylate

A mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (200 mg,1.19 mmol) and cyclohexyl amine (0.68 mL, 5.95 mmol) was heated at 50°C. for 16 hr. The mixture was concentrated in vacuum. The residue waspurified by flash column (0-100% EA in PE, 0.5% NH₃H₂O) to give thetitle compound (280 mg, 1.2597 mmol, 105.93% yield) as yellow oil.

LC-MS Method1 0.719 min, MS (m/z) 223.1 (M+H⁺).

1-cyclohexyl-1H-imidazole-4-carboxylic acid

To a mixture of ethyl 1-cyclohexyl-1H-imidazole-4-carboxylate (110 mg,0.4900 mmol) in THE (0.80 mL) and H₂O (1 mL) was added LiOH H₂O (0.09mL, 1.48 mmol), then stirred at 25° C. for 5 hr. TLC (100% EA) showednew spot (Rf=0) and the reactant was consumed completely. the aqueousphase was washed with DCM (3 mL×2) and acidified with 1N HCl to pH=2.The residual aqueous solution was lyophilized to give the title compound(190 mg, crude product) as pale yellow solid.

¹H NMR (400 MHz, Methanol-d₄) δ ppm 9.05 (s, 1H), 8.30 (s, 1H),4.36-4.30 (m, 1H), 2.20-2.17 (m, 2H), 1.92-1.82 (m, 2H), 1.80-1.73 (m,3H), 1.60-1.40 (m, 2H), 1.40-1.25 (m, 1H).

(1-cyclohexyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of 1-cyclohexyl-1H-imidazole-4-carboxylic acid (64.27 mg,0.2800 mmol) in DMF (0.50 mL) were added HATU (106.05 mg, 0.2800 mmol),DIPEA (0.18 mL, 1.11 mmol) and(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (50 mg, 0.2800 mmol). The resulting mixture was stirred at20° C. for 4 hr. The reaction mixture was diluted with H₂O (5 mL) andextracted with EtOAc (5 mL×2). The combined organic layers wereseparated, dried over Na₂SO₄ and concentrated in vacuum to give crudeoil. The crude oil was purified by prep-TLC (EA/MeOH=10/1) thenlyophilized to give the title compound (9.5 mg, 0.0267 mmol, 9.6077%yield) as white powder.

¹H NMR (400 MHz, DMSO-d₆) δ=7.77 (d, J=5.5 Hz, 2H), 4.58 (br d, J=12.0Hz, 1H), 4.14-4.02 (m, 1H), 3.93 (br d, J=12.0 Hz, 1H), 3.80 (br d,J=8.5 Hz, 1H), 3.51-3.43 (m, 1H), 2.64 (s, 2H), 2.05 (br s, 1H), 1.95(br d, J=12.3 Hz, 3H), 1.80 (br d, J=13.3 Hz, 2H), 1.72-1.61 (m, 3H),1.41-1.29 (m, 3H), 1.25 (s, 7H)

Example 9[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1,1,1-trifluoropropan-2-yl)-1H-imidazol-4-yl]methanoneethyl 1-(1,1,1-trifluoropropan-2-yl)-1H-imidazole-4-carboxylate

To a solution of 1,1,1-trifluoro-2-propanamine (403.4 mg, 3.57 mmol) in2-MeTHF (3 mL, 1.19 mmol) was added n-BuLi (1.43 mL, 3.57 mmol) at −78°C. The reaction mixture was stirred at −78° C. for 15 min. Then ethyl(2Z)-3-(dimethylamino)-2-isocyanoacrylate (200 mg, 1.19 mmol) was added.The reaction mixture was allowed to warm to 25° C. for 0.5 hr to giveblack solution. The reaction mixture was poured into EtOH (5 mL) andconcentrated.

The crude product was purified by flash column (PE to 100% EtOAc in PE).The afforded residue was purified by prep-TLC (EtOAc) to give the titlecompound (50 mg, 0.2117 mmol, 17.802% yield) as brown oil.

1-(1,1,1-trifluoropropan-2-yl)-1H-imidazole-4-carboxylic acid

To a solution of ethyl1-(1,1,1-trifluoropropan-2-yl)-1H-imidazole-4-carboxylate (50 mg, 0.2100mmol) in THF (1.5 mL) and H₂O (0.3 mL, 16.67 mmol) was addedhydroxylithium hydrate (26.65 mg, 0.6400 mmol). The mixture was stirredat 20° C. for 3 h to give black solution. LCMS showed the startingmaterial (50 mg, 0.2100 mmol) was remained. The mixture was stirred at40° C. for 12 h to give black solution. The reaction mixture wasconcentrated directly. The afforded H₂O layer was acidified with 1 N HClaq. to pH=5-6 and lyophilized to give the title compound (30 mg, 0.1441mmol, 68.086% yield) as brown solid.

[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1,1,1-trifluoropropan-2-yl)-1H-imidazol-4-yl]methanone

To a solution of1-(1,1,1-trifluoropropan-2-yl)-1H-imidazole-4-carboxylic acid (30 mg,0.1400 mmol) in DMF (1.5 mL) were added HATU (66.12 mg, 0.1700 mmol),DIPEA (0.12 mL, 0.7200 mmol). The mixture was stirred for 30 min. Then(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (36.48 mg, 0.1400 mmol) was added to the mixture. Themixture was stirred at 25° C. for 3 h to give brown solution. Thereaction mixture was concentrated directly. The residue was purified byprep-HPLC (NH₃) to give the title compound (16.87 mg, 0.0455 mmol,17.802% yield) as white powder.

LC-MS Method1: 371.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.72 (1H, s) 7.53 (1H, s) 4.59-4.78(2H, m) 4.19 (1H, dd, J=12.80, 5.77 Hz) 3.95 (1H, dd, J=12.05, 7.91,4.14 Hz) 3.63 (1H, br d, J=12.30 Hz) 2.65 (2H, s) 2.09 (1H, m d, J=3.76Hz) 2.01 (1H, m d, J=6.53 Hz) 1.76 (3H, d, J=7.28 Hz) 1.44-1.50 (1H, m)1.38 (6H, s)

Example 10[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-3-methylbutan-2-yl]-1H-imidazol-4-yl}methanone(R)-2-methyl-N-[(1E)-2-methylpropylidene]-2-propanesulfinamide

To a solution of (R)-t-BuS(O)NH₂ (8403.83 mg, 69.34 mmol) in THF (36.369mL) were added 2-methylpropanal (6.3 mL, 69.34 mmol) and Ti(OEt)₄ (21.57mL, 104.01 mmol) at 20° C. The resulting mixture was stirred at 60° C.for 0.5 hours to give yellow solution. H₂O (3 mL) was added dropwise andit was stirred at 20° C. for 5 mins, then it was filtered through a padof celite and concentrated in vacuum to give the title compound (8330mg, 47.521 mmol, 68.535% yield) as white solid. It was used directly forthe next step.

LC-MS Method1 0.825 min, MS (m/z) 176.2 (M+H⁺).

(R)-2-methyl-N-[(2S)-3-methyl-2-butanyl]-2-propanesulfinamide

To a stirred solution of(R)-2-methyl-N-[(1E)-2-methylpropylidene]-2-propanesulfinamide (2500 mg,14.26 mmol) in THF (30 mL) cooled to −40° C. was added MeMgBr (5.7 mL,17.11 mmol) dropwise. The reaction was stirred at −40° C. for 3 hr andwarmed up to 20° C. slowly over 13 hr. TLC (DCM/EA=6/1, RF=0.3) showedtwo new spot. H₂O (30 mL) was added and it was extracted with EtOAc (30mL×2). The combined organic layer dried over Na₂SO₄ and concentrated invacuum to give a yellow oil. The crude was purified by silica gelchromatography (PE/EA=10/1 to 3/1) to give the title compound (2200 mg,11.498 mmol, 80.623% yield) as colorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.35-3.10 (m, 1H), 2.90-2.75 (m,1H), 1.80-1.60 (m, 1H), 1.21 (d, J=6.8 Hz, 3H), 1.20 (s, 9H), 0.886 (d,J=6.8 Hz, 3H), 0.871 (d, J=6.8 Hz, H).

(2S)-3-methyl-2-butanamine

A solution of(R)-2-methyl-N-[(2S)-3-methyl-2-butanyl]-2-propanesulfinamide (2200 mg,11.5 mmol) in HCl/MeOH (10 mL, 40 mmol) was stirred at 20° C. for 4 hrto give a colorless solution. The reaction mixture was evaporated invacuum to give a white solid. It was triturated with toluene/PE=1/6 togive the title compound (1350 mg, 10.921 mmol) as white solid.

ethyl 1-[(2S)-3-methylbutan-2-yl]-1H-imidazole-4-carboxylate

To a 5 mL microwavevial were added (2S)-3-methyl-2-butanamine (500 mg,4.04 mmol), ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (680.27 mg,4.04 mmol), 1-Butanol (3 mL) and Et₃N (0.84 mL, 6.07 mmol). The reactionmixture was irradiated with microwave at 130° C. for 1 hr to give abrown solution. H₂O (30 mL) was added and it was extracted with EtOAc(30 mL×2). The combined organic layer dried over Na₂SO₄ and concentratedin vacuum to give a yellow oil. The crude was purified by silica gelchromatography (PE/EA=10/1 to 3/2) to give the title compound (161 mg,0.7657 mmol, 18.931% yield) as brown oil.

LC-MS Method1 0.691 min, MS (m/z) 211.2 (M+H⁺).

1-[(2S)-3-methylbutan-2-yl]-1H-imidazole-4-carboxylic acid

A stirred solution of ethyl1-[(2S)-3-methylbutan-2-yl]-1H-imidazole-4-carboxylate (150.0 mg, 0.7600mmol) in 1,4-Dioxane (3 mL) was added a solution of LiOH.H₂O (48.11 mg,1.15 mmol). The reaction mixture was stirred at 20° C. for 4 hr to givea yellow solution. H₂O (10 mL) was added and it was extracted with EtOAc(10 mL×2). The H₂O phase was adjusted to 5 with 1M HCl aq. andlyophilized to give the title compound (110 mg, 0.6037 mmol, 78.98%yield) as brown solid.

LC-MS Method1 0.306 min, MS (m/z) 183.0 (M+H⁺).

[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-3-methylbutan-2-yl]-1H-imidazol-4-yl}methanone

To a stirred solution of1-[(2S)-3-methylbutan-2-yl]-1H-imidazole-4-carboxylic acid (100 mg,0.5500 mmol) and HATU (251.76 mg, 0.6600 mmol) in DMF (3 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.47 mL, 2.74 mmol). After stirredfor 30 mins,(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (138.94 mg, 0.5500 mmol) was added and the reaction wasstirred at 20° C. for 16 hr to give a yellow solution. H₂O (30 mL) wasadded and it was extracted with EtOAc (30 mL×2). The combined organiclayer dried over Na₂SO₄ and concentrated in vacuum to give a yellow oil.The crude was purified by Prep-HPLC (NH₃) and lyophilized to give thetitle compound (108.71 mg, 0.3156 mmol, 57.509% yield) as white solid.

LC-MS Method1: 345.3 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.61 (d, J=1.00 Hz, 1H), 7.40 (d,J=1.25 Hz, 1H), 4.76 (br d, J=12.05 Hz, 1H), 4.18 (d, J=12.55 Hz, 1H),3.94 (br dd, J=4.02, 11.80 Hz, 1H), 3.84 (quin, J=7.09 Hz, 1H), 3.61(dd, J=4.27, 12.55 Hz, 1H), 2.64 (s, 2H), 2.07 (br dd, J=3.51, 7.28 Hz,1H), 1.95-1.99 (m, 1H), 1.87-1.94 (m, 1H), 1.47 (d, J=6.78 Hz, 4H), 1.36(s, 6H), 0.96 (d, J=6.78 Hz, 3H), 0.78 (d, J=6.53 Hz, 3H)

Example 11{1-[(2R)-butan-2-yl]-1H-imidazol-4-yl}[(1R,5S,6R)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanoneethyl 1-[(2R)-butan-2-yl]-1H-imidazole-4-carboxylate

A mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (300 mg,1.78 mmol) and (2R)-2-butanamine (0.54 mL, 5.35 mmol) was stirred at 50°C. for 16 h to give brown mixture. TLC (PE:EA=1:1) showed new spot(Rf=0.2) was detected. The mixture was concentrated to give a residue.The residue was purified by flash column (PE:EA=1:0 to 1:4) to affordthe title compound (240 mg, 1.2229 mmol, 68.562% yield) as brown solid.

LC-MS Method1 0.586 min, MS (m/z) 196.9 (M+H⁺).

1-[(2R)-butan-2-yl]-1H-imidazole-4-carboxylic acid

To a mixture of ethyl 1-[(2R)-butan-2-yl]-1H-imidazole-4-carboxylate(240 mg, 1.22 mmol) in THF (3 mL) and H₂O (1.5 mL) was added LiOH.H₂O(0.11 mL, 1.83 mmol). The reaction mixture was stirred at 25° C. for 16h to give yellow mixture. TLC (PE:EtOAc=1:1) showed most of the startingmaterial was consumed. The reaction mixture was diluted with H₂O (15 mL)and extracted with EtOAc (8 mL×5). The aqueous phase was acidified with1 N HCl aq. to pH=4. The resulting aqueous phase was dried in vacuum toafford the title compound (200 mg, 1.1891 mmol, 97.236% yield) (crude)as yellow oil.

{1-[(2R)-butan-2-yl]-1H-imidazol-4-yl}[(1R,5S,6R)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (70 mg, 0.3900 mmol) in DMF (1 mL) were added1-[(2R)-butan-2-yl]-1H-imidazole-4-carboxylic acid (65.32 mg, 0.3900mmol), DIPEA (0.26 mL, 1.55 mmol) and HATU (178.16 mg, 0.4700 mmol). Thereaction mixture was stirred at 25° C. for 16 h to give brown mixture.The reaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (NH₃). The afforded flows werecombined, concentrated to remove most of CH₃CN and lyophilized to affordthe title compound (4.09 mg, 0.0108 mmol, 2.7864% yield) as yellowsolid.

LC-MS Method1: 331.1 [M+H⁺]

¹H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (br s, 1H), 8.19 (br s, 1H),4.31-4.44 (m, 1H), 4.15 (br d, J=11.3 Hz, 1H), 3.96 (br d, J=12.8 Hz,1H), 3.90 (br d, J=9.0 Hz, 1H), 3.50-3.65 (m, 1H), 2.65 (s, 2H), 2.16(br d, J=3.3 Hz, 1H), 2.07 (br d, J=3.5 Hz, 1H), 1.82 (quin, J=7.2 Hz,2H), 1.55 (t, J=3.4 Hz, 1H), 1.48 (d, J=6.8 Hz, 3H), 1.26 (s, 6H), 0.76(t, J=7.4 Hz, 3H)

Example 12{1-[(2S)-butan-2-yl]-11-imidazol-4-yl}[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

ethyl 1-[(2S)-butan-2-yl]-1H-imidazole-4-carboxylate

A mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (300 mg,1.78 mmol) and (S)-butan-2-amine (0.54 mL, 5.35 mmol) was stirred at 50°C. for 12 h to give brown mixture. TLC(PE:EA=1:1) showed new spot(Rf=0.2) was detected. The mixture was concentrated to give a residue.The residue was purified by flash column (PE:EA=1:0 to 1:4) to affordthe title compound (160 mg, 0.8153 mmol, 45.708% yield) as yellow solid.

LC-MS Method1 0.580 min, MS (m/z) 196.1 (M+H⁺).

1-[(2S)-butan-2-yl]-1H-imidazole-4-carboxylic acid

To a mixture of ethyl 1-[(2S)-butan-2-yl]-1H-imidazole-4-carboxylate(160 mg, 0.8200 mmol) in THF (4 mL) and H₂O (2 mL) was added LiOH.H₂O(0.07 mL, 1.22 mmol). The reaction mixture was stirred at 20° C. for 16h to give yellow mixture. The reaction mixture was diluted with H₂O (15mL) and extracted with EtOAc (8 mL×5). The aqueous phase was acidifiedwith 1 N HCl aq. to pH=4. The resulting aqueous phase was dried invacuum to afford the title compound (150 mg, 0.8918 mmol, 109.39% yield)(crude) as yellow solid.

{1-[(2S)-butan-2-yl]-1H-imidazol-4-yl}[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (70 mg, 0.3900 mmol) in DMF (1.5 mL) were added1-[(2S)-butan-2-yl]-1H-imidazole-4-carboxylic acid (65.32 mg, 0.3900mmol), DIPEA (0.26 mL, 1.55 mmol) and HATU (178.16 mg, 0.4700 mmol). Thereaction mixture was stirred at 25° C. for 16 h to give brown mixture.LCMS showed the starting material was consumed. The reaction mixture wasfiltered. The filtrate was purified by prep-HPLC (NH₃). The affordedflows were combined, concentrated to remove most of CH₃CN andlyophilized to afford the title compound (34.59 mg, 0.1002 mmol, 25.797%yield) as white solid.

LC-MS Method2 1.516 min, MS (m/z) 331.2 [M+H⁺]¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.64 (s, 1H), 7.44 (s, 1H), 4.76(br d, J=12.0 Hz, 1H), 4.19 (br d, J=12.5 Hz, 1H), 4.02-4.10 (m, 1H),3.95 (br d, J=7.8 Hz, 1H), 3.58-3.65 (m, 1H), 2.64 (s, 2H), 2.08 (br s,1H), 1.93-2.01 (m, 1H), 1.93-2.01 (m, 1H), 1.74-1.84 (m, 2H), 1.49 (d,J=6.8 Hz, 3H), 1.47 (br s, 1H), 1.37 (s, 6H), 0.85 (t, J=7.4 Hz, 3H)

Example 13[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-4-methylpentan-2-yl]-1H-imidazol-4-yl}methanone(R)-2-methyl-N-[(2E)-1,3-dimethylbutanylidene]-2-propanesulfinamide

To a mixture of 4-methyl-2-pentanone (1.25 mL, 9.98 mmol) in THF (10 mL)were added (R)-2-methylpropane-2-sulfinamide (1210.06 mg, 9.98 mmol) andTi(OEt)₄ (3414.54 mg, 14.98 mmol). The reaction mixture was stirred at60° C. for 2 h to give colorless mixture. The reaction mixture wasdiluted with EtOAc (30 mL). The mixture was added to H₂O (10 mL) andstirred for 1 min to give yellow suspension. The suspension wasfiltered. The filtrate was washed with H₂O (20 mL×3), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum to afford thetitle compound (900 mg, 4.4261 mmol, 44.332% yield) as colorless oil.

LC-MS Method1 0.778 min, MS (m/z) 204.0 (M+H).

(R)-2-methyl-N-[(2S)-4-methylpentan-2-yl]-2-propanesulfinamide

To a mixture of(R)-2-methyl-N-[(2E)-1,3-dimethylbutanylidene]-2-propanesulfinamide (900mg, 4.43 mmol) in THF (9 mL) was added L-selectride (13.28 mL, 13.28mmol) at 0° C. The reaction mixture was stirred at 25° C. for 2 h togive colorless mixture. TLC (PE:EtOAc=2:1) showed one new spot (Rf=0.2)was detected. The reaction quenched by H₂O (3 mL). The reaction mixturewas concentrated in vacuo to give a residue. The residue was purified byflash column (PE to 30% EtOAc in PE) to afford the title compound (260mg, 1.026 mmol, 45.252% yield) as colorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.50-3.30 (m, 1H), 2.81 (d, J=8.0Hz, 1H), 1.80-1.60 (m, 1H), 1.60-1.30 (m, 2H), 1.28 (d, J=6.4 Hz, 3H),1.21 (s, 9H), 0.90 (d, J=6.8 Hz, 3H), 0.88 (d, J=6.8 Hz, 3H).(2S)-4-methyl-2-pentanamine hydrochloride

A solution of(R)-2-methyl-N-[(2S)-4-methylpentan-2-yl]-2-propanesulfinamide (610 mg,2.97 mmol) in MeOH/HCl (10 mL, 2.97 mmol) was stirred at 25° C. for 2 hto give colorless mixture. The reaction mixture was concentrated invacuo to give a residue. The residue was triturated with PE (20 mL) anddried in vacuo to give the title compound (240 mg, 1.7436 mmol, 58.698%yield) as white solid.

ethyl 1-[(2S)-4-methylpentan-2-yl]-1H-imidazole-4-carboxylate

To a mixture of (2S)-4-methyl-2-pentanamine hydrochloride (240 mg, 1.74mmol) in 1-Butanol (2.5 mL) were added ethyl(2Z)-3-(dimethylamino)-2-isocyanoacrylate (293.25 mg, 1.74 mmol) andEt₃N (0.34 mL, 2.62 mmol). The reaction mixture was stirred at 130° C.for 1 h with a microwave system to give brown mixture. TLC(PE:EtOAc=1:1) showed one new spot (Rf=0.2) was detected. The reactionmixture was concentrated in vacuo to give a residue. The residue waspurified by prep-TLC (PE:EtOAc=1:1) to afford the title compound (60 mg,0.2675 mmol, 15.342% yield) as yellow oil.

LC-MS Method1 0.681 min, MS (m/z) 225.0 (M+H⁺).

1-[(2S)-4-methylpentan-2-yl]-1H-imidazole-4-carboxylic acid

To a mixture of ethyl1-[(2S)-4-methylpentan-2-yl]-1H-imidazole-4-carboxylate (60 mg, 0.2700mmol) in THF (1.5 mL) and H₂O (0.50 mL) was added LiOH.H₂O (0.02 mL,0.4000 mmol). The reaction mixture was stirred at 40° C. for 16 h togive a yellow mixture. TLC (PE:EtOAc=1:1) showed the starting materialwas consumed completely. The reaction mixture was diluted with H₂O (5mL) and extracted with EtOAc (3 mL×2). The aqueous phase was acidifiedwith 1 N HCl aq. to pH=5 and lyophilized to afford the title compound(50 mg, 0.2548 mmol, 95.244% yield) as yellow solid.

[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-4-methylpentan-2-yl]-1H-imidazol-4-yl}methanone

To a mixture of 1-[(2S)-4-methylpentan-2-yl]-1H-imidazole-4-carboxylicacid (50 mg, 0.2500 mmol) in Pyridine (2.5 mL) was added EDCI (58.61 mg,0.3100 mmol). The mixture was stirred at 25° C. for 10 min and followedby addition of(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (55.21 mg, 0.2500 mmol). The mixture was allowed tostirred at 25° C. for 16 h to give a yellow mixture. LCMS showed thestarting material was consumed completely. The reaction mixtureconcentrated in vacuo to give a residue. The residue was purified byprep-HPLC (NH₃). The afforded flows were combined, concentrated toremove most of CH₃CN and lyophilized to afford the title compound (16.26mg, 0.0449 mmol, 17.643% yield) as yellow solid.

LC-MS Method1: 359.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.64 (s, 1H), 7.46 (s, 1H), 4.76(br d, J=12.0 Hz, 1H), 4.13-4.33 (m, 2H), 3.95 (dd, J=12.0, 3.8 Hz, 1H),3.62 (dd, J=12.3, 4.0 Hz, 1H), 2.64 (s, 2H), 2.08 (br d, J=3.5 Hz, 1H),1.98 (br d, J=3.5 Hz, 1H), 1.68-1.78 (m, 1H), 1.50-1.57 (m, 2H), 1.47(d, J=6.8 Hz, 4H), 1.38 (s, 6H), 0.92 (d, J=6.5 Hz, 3H), 0.87 (d, J=6.8Hz, 3H)

Example 14(1-((S)-1-cyclopropylethyl)-1H-imidazol-4-yl)((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)methanoneethyl 1-[(1S)-1-cyclopropylethyl]-1H-imidazole-4-carboxylate

Around bottom flask was charged with (S)-1-cyclopropylethanaminehydrochloride (903.81 mg, 7.43 mmol), Et₃N (1.57 mL, 11.15 mmol), ethyl(2Z)-3-(dimethylamino)-2-isocyanoacrylate (250 mg, 1.49 mmol) and1-Butanol (0.50 mL). The resulting mixture was stirred at 70° C. for 36hours to give yellow solution. The reaction mixture was poured into H₂O(30 mL) and extracted with EtOAc (30 mL×2). The combined organic layerswere washed with brine (30 mL×2), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a yellow oil. The crudeproduct was purified by flash column (PE to 100% EtOAc in PE) to givethe title compound (100 mg, 0.4802 mmol, 32.304% yield) as yellow oil.

LC-MS Method1 0.652 min, MS (m/z) 209.2 (M+H⁺).

1-[(1S)-1-cyclopropylethyl]-1H-imidazole-4-carboxylic acid

To a solution of ethyl1-[(1S)-1-cyclopropylethyl]-1H-imidazole-4-carboxylate (150 mg, 0.7200mmol) in H₂O (0.50 mL), THF (0.50 mL), MeOH (0.50 mL) was addedhydroxylithium hydrate (60.44 mg, 1.44 mmol). The resulting mixture wasstirred at 20-25° C. for 14 hours to give white suspension. The reactionmixture was poured into H₂O and extracted with EtOAc (20 mL×4). Thecombined organic layers were washed with brine (20 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thetitle compound (150 mg, crude product) as yellow oil.

LC-MS Method1 0.227 min, MS (m/z) 180.9 (M+H⁺).

(1-((S)-1-cyclopropylethyl)-1H-imidazol-4-yl)((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone

To a solution of 1-[(1S)-1-cyclopropylethyl]-1H-imidazole-4-carboxylicacid (70 mg, 0.3900 mmol) in DMF (3 mL) were added HATU (193.06 mg,0.5000 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.94 mmol)at 20° C. for 30 min.(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (98.35 mg, 0.3900 mmol) was added. The resulting mixturewas stirred at 20-25° C. for 14 hours to give yellow solution. Thereaction mixture was poured into sat. NH₄Cl aq. (50 mL) and extractedwith EtOAc (50 mL×4). The combined organic layers were washed with brine(50 mL×2), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by prep-HPLC (FA) to give the titlecompound (10.65 mg, 0.0311 mmol, 8.0061% yield) as yellow oil.

LC-MS Method1: 343.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) S=7.70 (s, 1H), 7.64 (s, 1H), 4.63 (br d,J=10.0 Hz, 1H), 4.19 (br d, J=12.5 Hz, 1H), 3.95 (br dd, J=3.4, 11.2 Hz,1H), 3.63 (br d, J=11.5 Hz, 1H), 3.48-3.43 (m, 1H), 2.64 (s, 2H), 2.08(br s, 2H), 1.58 (d, J=6.8 Hz, 3H), 1.47 (t, J=3.4 Hz, 1H), 1.36 (s,6H), 1.19-1.13 (m, 1H), 0.75-0.61 (m, 2H), 0.36 (q, J=4.9 Hz, 2H)

Example 15{1-[(1R)-1-cyclopropylethyl]-1H-imidazol-4-yl}[(1R,5S,6R)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanoneethyl 1-[(1R)-1-cyclopropylethyl]-1H-imidazole-4-carboxylate

To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (500mg, 2.97 mmol) in 1-Butanol (1 mL) was added(1R)-1-cyclopropylethanamine (253.14 mg, 2.97 mmol) at 20° C. Thereaction mixture was irradiated with microwave at 130° C. for 40 min togive a yellow solution. The reaction mixture was poured into sat. NH₄Claq. (50 mL) and extracted with EtOAc (50 mL×4). The combined organiclayers were washed with sat. aq. (50 mL×2), dried over Na₂SO₄, filteredand concentrated under reduced pressure. The crude product was purifiedby silica column (PE to PE:EtOAc=1:1) to give the title compound (190mg, 0.9123 mmol, 30.689% yield) as yellow oil.

LC-MS Method1 0.608 min, MS (m/z) 209.0 (M+H).

1-[(1R)-1-cyclopropylethyl]-1H-imidazole-4-carboxylic acid

To a solution of ethyl1-[(1R)-1-cyclopropylethyl]-1H-imidazole-4-carboxylate (190 mg, 0.9100mmol) in H₂O (1.9 mL), THE (1.9 mL), MeOH (1.9 mL) was addedhydroxylithium hydrate (76.56 mg, 1.82 mmol) at 20° C. The resultingmixture was stirred at 20-25° C. for 2 hours to give white suspension.The reaction mixture was poured into H₂O and extracted with EtOAc (20mL×4). The combined organic layers were washed with sat. aq. (20 mL×2),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the title compound (180 mg, 0.9989 mmol, 109.49% yield) as yellowoil.

LC-MS Method1 0.214 min, MS (m/z) 180.0 (M+H⁺).

{1-[(1R)-1-cyclopropylethyl]-1H-imidazol-4-yl}[(1R,5S,6R)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 1-[(1R)-1-cyclopropylethyl]-1H-imidazole-4-carboxylicacid (70 mg, 0.3900 mmol) in DMF (2 mL) were added HATU (193.06 mg,0.5000 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.33 mL, 1.94 mmol)at 20° C. The reaction mixture was stirred for 30 min.(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (98.35 mg, 0.3900 mmol) was added. The resulting mixturewas stirred at 20-25° C. for 14 hours to give yellow solution. Thereaction mixture was poured into sat. NH₄Cl aq. (50 mL) and extractedwith EtOAc (50 mL×4). The combined organic layers were washed with sat.aq. (50 mL×2), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by prep-HPLC (FA) to give thetitle compound (14.08 mg, 0.0411 mmol, 10.585% yield) as yellow oil.

LC-MS Method1: 343.3 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.70 (d, J=1.3 Hz, 1H), 7.64 (s, 1H),4.65 (br d, J=11.5 Hz, 1H), 4.19 (br d, J=12.3 Hz, 1H), 3.94 (br dd,J=3.8, 11.8 Hz, 1H), 3.62 (br dd, J=4.1, 12.4 Hz, 1H), 3.45 (dd, J=6.8,8.8 Hz, 1H), 2.64 (s, 2H), 2.11-2.05 (m, 2H), 1.58 (d, J=6.8 Hz, 3H),1.46 (t, J=3.4 Hz, 1H), 1.36 (s, 6H), 1.19-1.13 (m, 1H), 0.77-0.70 (m,1H), 0.65-0.60 (m, 1H), 0.36 (q, J=5.4 Hz, 2H)

Example 16(1-((S)-1-cyclobutylethyl)-1H-imidazol-4-yl)((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone(R)—N—[(E)-cyclobutylmethylene]-2-methyl-2-propanesulfinamide

To a mixture of cyclobutane aldehyde (1.07 mL, 11.89 mmol) in THF (15mL) were added (R)-2-methylpropane-2-sulfinamide (1.44 g, 11.89 mmol)and Ti(OEt)₄ (4065.62 mg, 17.83 mmol). The reaction mixture was stirredat 60° C. for 2 h to give yellow mixture. TLC(PE:EtOAc=10:1) showed thestarting material was consumed completely, one new spot was (Rf=0.2)detected. The reaction mixture was diluted with EtOAc (40 mL). Themixture was added to H₂O (10 mL) and stirred for 1 min to give whitesuspension. The suspension was filtered. The filtrate was washed withH₂O (20 mL×3), dried with anhydrous Na₂SO₄, filtered and concentrated invacuum to afford the title compound

(1.77 g, 9.4501 mmol, 79.494% yield) as colorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.12 (d, J=4.8 Hz, 1H), 3.45-3.30 (m,1H), 2.35-2.10 (m, 4H), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 1H), 1.20 (s,9H). (R)—N-[(1S)-1-cyclobutylethyl]-2-methyl-2-propanesulfinamide

To a solution of(R)—N—[(E)-cyclobutylmethylene]-2-methyl-2-propanesulfinamide (0.5 g,2.67 mmol) in THF (6 mL) was added chloro(methyl)magnesium (2.67 mL,8.01 mmol) at −40° C. The reaction mixture was stirred at −40° C. for 2h to give yellow mixture. TLC (DCM:EtOAc=1:1) showed the startingmaterial was consumed completely, one new spot (Rf=0.3) was detected.The reaction mixture quenched with NH₄C1 (eq., 25 mL) and then extractedwith EtOAc (15 mL×3). The combined organic phase was washed with brine(20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuoto give a residue. The residue was purified by flash column (DCM to 20%EtOAc in DCM) to afford the title compound (360 mg, 1.7704 mmol, 66.32%yield) as colorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.35-3.15 (m, 1H), 2.84 (d, J=8.0 Hz,1H), 2.40-2.20 (m, 1H), 2.10-1.90 (m, 1H), 2.00-1.90 (m, 1H), 1.90-1.60(m, 4H), 1.20 (s, 9H), 1.18 (d, J=6.8 Hz, 3H).(1S)-1-cyclobutylethanamine hydrochloride

A solution of(R)—N-[(1S)-1-cyclobutylethyl]-2-methyl-2-propanesulfinamide (360 mg,1.77 mmol) in MeOH/HCl (0.44 mL, 1.77 mmol) was stirred at 25° C. for 2h to give colorless mixture. TLC (DCM:EtOAc=1:1) showed the startingmaterial was consumed completely. The reaction mixture was concentratedin vacuo to give the title compound (330 mg, 2.4329 mmol, 137.42% yield)as yellow solid.

ethyl 1-[(1S)-1-cyclobutylethyl]-1H-imidazole-4-carboxylate

To a mixture of (1S)-1-cyclobutylethanamine hydrochloride (240 mg, 1.77mmol) in 1-Butanol (2 mL) were added ethyl(2Z)-3-(dimethylamino)-2-isocyanoacrylate (297.59 mg, 1.77 mmol) andEt₃N (0.37 mL, 2.65 mmol). The reaction mixture was stirred at 130° C.for 1 h used MW to give brown mixture. LCMS showed the starting materialwas consumed completely. TLC (PE:EtOAc=2:1) showed one new spot (Rf=0.2)was detected. The reaction mixture was concentrated in vacuo to give aresidue. The residue was purified by prep-TLC (100% EtOAc) to afford thetitle compound (36 mg, 0.1620 mmol, 9.1533% yield) as brown solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.61 (s, 1H), 7.50 (s, 1H), 4.37 (q,J=6.8 Hz, 2H), 4.15-4.00 (m, 1H), 2.70-2.50 (m, 1H), 2.20-2.10 (m, 1H),2.00-1.60 (m, 5H), 1.40 (d, J=6.8 Hz, 3H), 1.39 (t, J=6.8 Hz, 3H).1-[(1S)-1-cyclobutylethyl]-1H-imidazole-4-carboxylic acid

To a mixture of ethyl1-[(1S)-1-cyclobutylethyl]-1H-imidazole-4-carboxylate (36 mg, 0.1600mmol) in THF (1.5 mL) and H₂O (0.50 mL) was added LiOH.H₂O (0.01 mL,0.2400 mmol). The reaction mixture was stirred at 25° C. for 16 h togive brown mixture. TLC(PE:EtOAc=1:1) showed the starting material wasconsumed completely. The reaction mixture was diluted with H₂O (4 mL)and extracted with EtOAc (2 mL×2). The aqueous phase was acidified with1 N HCl aq. to pH=4 and lyophilized to the title compound (31 mg, 0.1596mmol, 98.547% yield) as brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ=7.91 (s, 1H), 7.84 (s, 1H), 4.40-4.20 (m,1H), 2.75-2.65 (m, 1H), 2.15-2.00 (m, 1H), 1.95-1.60 (m, 5H), 1.38 (d,J=6.8 Hz, 3H).

(1-((S)-1-cyclobutylethyl)-1H-imidazol-4-yl)((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone

To a solution of 1-[(1S)-1-cyclobutylethyl]-1H-imidazole-4-carboxylicacid (30 mg, 0.1500 mmol) in DMF (1.5 mL) were added HATU (70.86 mg,0.1900 mmol), DIPEA (99.81 mg, 0.7700 mmol). The mixture was stirred for10 min. Then(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (39.1 mg, 0.1500 mmol) was added to the mixture. Themixture was stirred at 25° C. for 12 h to give brown solution. Thereaction mixture was concentrated directly. The residue was purified byprep-HPLC (NH₃) to give the title compound (25.52 mg, 0.0716 mmol,46.352% yield) as brown solid.

LC-MS Method1: 357.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (1H, d, J=1.25 Hz), 7.42 (1H,d, J=1.25 Hz), 4.76 (1H, d, J=12.05 Hz), 4.19 (1H, d, J=12.55 Hz),3.99-4.08 (1H, m), 3.94 (1H, dd, J=12.17, 4.14 Hz), 3.61 (1H, dd,J=12.55, 4.27 Hz), 2.64 (2H, s), 2.53-2.63 (1 H, m), 2.05-2.18 (2H, m),1.94-2.01 (1H, m), 1.85-1.94 (2H, m), 1.67-1.84 (3H, m), 1.46 (1H, brs), 1.36-1.41 (9H, m)

Example 17{1-[(1R)-1-cyclobutylethyl]-1H-imidazol-4-yl}[(1R,5S,6R)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanoneethyl 1-[(1R)-1-cyclobutylethyl]-1H-imidazole-4-carboxylate

To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (100mg, 0.5900 mmol) in Et₃N (0.58 mL, 4.46 mmol) was added the mixture of(1R)-1-cyclobutylethanamine hydrochloride (241.94 mg, 1.78 mmol) in1-Butanol (0.30 mL). The resulting mixture was stirred at 70° C. for 16hours to give yellow mixture. TLC (PE:EtOAc=1:1) showed one new spot(Rf=0.3) was detected. The reaction mixture was concentrated in vacuo togive a residue. The residue was purified by prep-TLC (PE:EtOAc=1:1) toafford the title compound (25 mg, 0.1125 mmol, 18.916% yield) as yellowoil.

LC-MS Method1 0.667 min, MS (m/z) 222.9 (M+H⁺).

1-[(1R)-1-cyclobutylethyl]-1H-imidazole-4-carboxylic acid

To a mixture of ethyl1-[(1R)-1-cyclobutylethyl]-1H-imidazole-4-carboxylate (25 mg, 0.1100mmol) in THF (0.75 mL) and H₂O (0.25 mL) was added LiOH.H₂O (0.01 mL,0.1700 mmol). The reaction mixture was stirred at 40° C. for 16 h togive yellow mixture. TLC (PE:EtOAc=1:1) showed starting material wasconsumed completely. The reaction mixture was diluted with H₂O (6 mL)and concentrated to remove most of THF. The aqueous phase was acidifiedwith 1 N HCl aq. to pH=5 and lyophilized to afford the title compound(21 mg, 0.1081 mmol, 96.131% yield) as yellow solid.

LC-MS Method1 0.414 min, MS (m/z) 194.9 (M+H⁺).

{1-[(1R)-1-cyclobutylethyl]-1H-imidazol-4-yl}[(1R,5S,6R)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of 1-[(1R)-1-cyclobutylethyl]-1H-imidazole-4-carboxylicacid (21 mg, 0.1100 mmol) in DMF (0.50 mL) were added HATU (49.6 mg,0.1300 mmol) and DIPEA (0.09 mL, 0.5400 mmol). The mixture was stirredat 50° C. for 30 min and followed by addition of(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (29.23 mg, 0.1600 mmol). The mixture was stirred at 25° C.for 16 h to give a yellow mixture. The reaction mixture was purified byprep-HPLC (NH₃). The afforded flows were combined, concentrated toremove most of CH₃CN and lyophilized to afford the title compound (1.64mg, 0.0046 mmol, 4.2553% yield) as yellow solid.

LC-MS Method1: 357.1 [M+H⁺]

¹H NMR (400 MHz, METHANOL-d4) δ ppm 7.73 (s, 1H), 7.68 (s, 1H), 4.42 (brd, J=11.3 Hz, 1H), 4.18-4.29 (m, 1H), 4.11 (br d, J=12.8 Hz, 1H), 3.94(br dd, J=12.2, 3.9 Hz, 1H), 3.60 (br dd, J=12.4, 3.6 Hz, 1H), 2.73 (s,2H), 2.62-2.71 (m, 1H), 2.10-2.20 (m, 2H), 2.03-2.10 (m, 1H), 1.78-1.94(m, 4H), 1.72 (br t, J=8.5 Hz, 1H), 1.49 (t, J=3.4 Hz, 1H), 1.40 (d,J=6.5 Hz, 3H), 1.34 (s, 6H), 0.89 (br d, J=9.8 Hz, 1H)

Example 18(1-((S)-1-cyclopentylethyl)-1H-imidazol-4-yl)((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone(1-((S)-1-cyclopentylethyl)-1H-imidazol-4-yl)((1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone

To a solution of 1-[(1S)-1-cyclopentylethyl]-1H-imidazole-4-carboxylicacid (50 mg, 0.2400 mmol, prepared with the same protocol described inExample 19 using (R)-2-methylpropane-2-sulfinamide in stead of(S)-2-methylpropane-2-sulfinamide) in DMF (5 mL) were added HATU (137.68mg, 0.3600 mmol) and Et₃N (0.12 mL, 0.9600 mmol). The mixture wasstirred at 25° C. for 30 min. Then(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (43.28 mg, 0.2400 mmol) was added. The resulting mixturewas stirred at 25° C. for 3 hours to give a brown solution. The reactionmixture was concentrated in vacuum to remove most of DMF. The crudeproduct was purified by Prep-HPLC (NH₃) and lyophilized to give thetitle compound (70 mg, 0.1889 mmol, 78.697% yield) as a white solid.

LC-MS Method1: 371.3 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.65 (d, J=1.1 Hz, 1H), 7.44 (d, J=0.9Hz, 1H), 4.76 (br d, J=11.9 Hz, 1H), 4.19 (br d, J=12.6 Hz, 1H), 3.95(br dd, J=3.9, 11.9 Hz, 1H), 3.87 (qd, J=6.8, 9.5 Hz, 1H), 3.62 (br dd,J=4.1, 12.5 Hz, 1H), 3.66-3.57 (m, 1H), 2.64 (s, 2H), 2.20-2.04 (m, 2H),2.02-1.94 (m, 1H), 1.88 (dtd, J=3.9, 7.6, 11.7 Hz, 1H), 1.64-1.55 (m,3H), 1.49 (d, J=6.8 Hz, 6H), 1.38 (s, 6H), 1.23 (qd, J=8.8, 12.6 Hz,1H), 1.14-1.01 (m, 1H)

Example 19{1-[(1R)-1-cyclopentylethyl]-1H-imidazol-4-yl}[(1R,5S,6R)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(S)—N—[(E)-cyclopentylmethylene]-2-methyl-2-propanesulfinamide

To a mixture of cyclopentyl aldehyde in THF (20 mL) were added(S)-2-methylpropane-2-sulfinamide (2.47 g, 20.38 mmol), titanium(IV)ethanolate (6.97 g, 30.57 mmol). The suspension was stirred at 20° C.for 16 hr. The reaction mixture was diluted with EtOAc (60 mL). Themixture was added to H₂O (10 mL) and stirred for 1 min to give whitesuspension. The suspension was filtered. The filtrate was washed withH₂O (30 mL×3), dried with anhydrous Na₂SO₄, filtered and concentrated invacuum to afford compound the title compound (3.6 g, crude) as yellowliquid.

LC-MS Method1: 0.833 min, MS (m/z): 201.9 (M+H⁺).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.92 (t, d=4.8 Hz, 1H), 2.90-2.80(m, 1H), 1.90-1.75 (m, 3H), 1.75-1.50 (m, 5H), 1.15 (s, 9H).

(S)—N-[(1R)-1-cyclopentylethyl]-2-methyl-2-propanesulfinamide

To a mixture of(S)—N—[(E)-cyclopentylmethylene]-2-methyl-2-propanesulfinamide in THF(20 mL) was added MeMgCl (742.96 mg, 9.93 mmol, 3.31 mL) dropwise for 10min at −40° C. under N₂. The suspension was stirred at 20° C. for 16 hr.The residue was diluted with NH₄Cl (15 mL), extracted with EtOAc (30mL×4), washed with saturated NaCl (30 mL×2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The solution was purifiedby flash column (PE to 30% EtOAc in PE) to afford the title compound(595 mg, crude) as yellow liquid.

LC-MS Method1: 0.827 min, MS (m/z): 218 (M+H⁺).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.20-3.05 (m, 1H), 2.82 (brd, J=8.4Hz, 1H), 1.90-1.40 (m, 8H), 1.20 (d, J=7.2 Hz, 3H), 1.14 (s, 9H).

(1R)-1-cyclopentylethanamine hydrochloride

To a mixture of(S)—N-[(1R)-1-cyclopentylethyl]-2-methyl-2-propanesulfinamide was addedMeOH/HCl (5 mL). The suspension was stirred at 25° C. for 1 hr. Theresidue was concentrated in vacuum to afford the title compound (257 mg,crude) as yellow solid.

ethyl 1-[(1R)-1-cyclopentylethyl]-1H-imidazole-4-carboxylate

To a mixture of (1R)-1-cyclopentylethanamine hydrochloride (52.0 mg,0.35 mmol) was added 1-Butanol (0.5 mL). Then ethyl(2Z)-3-(dimethylamino)-2-isocyanoacrylate (58.44 mg, 0.35 mmol), Et₃N(52.64 mg, 0.52 mmol, 0.07 mL) was added into the solution. Thesuspension was subjected to reaction in microwave reactor (time: 1 hr,temp: 130° C.). The residue was concentrated in vacuum to affordcompound the title compound (77 mg, crude) as yellow oil.

LC-MS Method1: 0.690 min, MS (m/z): 237.0 (M+H⁺).

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.57 (s, 1H), 7.43 (s, 1H), 4.30(q, J=6.8 Hz, 2H), 3.80-3.70 (m, 1H), (q, J=7.2 Hz, 2H), 1.70-1.40 (m,8H), 1.42 (d, J=6.8 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).1-[(1R)-1-cyclopentylethyl]-1H-imidazole-4-carboxylic acid

To a mixture of ethyl1-[(1R)-1-cyclopentylethyl]-1H-imidazole-4-carboxylate in H₂O (0.5 mL)and THF (1.5 mL) was added LiOH.H₂O (20.5 mg, 0.49 mmol, 1.5 eq). Thesuspension was stirred at 20° C. for 2 hr. The residue was diluted withH₂O (1 mL), extracted with EtOAc (5 mL×4). The afforded H₂O layer wasbasified with 1 N HCl aq. to pH=5. The combined organic layers wereconcentrated and then lyophilized to afford compound the title compound(39 mg, crude) as yellow soild.

LC-MS Method1: 0.571 min, MS (m/z): 209 (M+H⁺).

{1-[(1R)-1-cyclopentylethyl]-1H-imidazol-4-yl}[(1R,5S,6R)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of 1-[(1R)-1-cyclopentylethyl]-1H-imidazole-4-carboxylicacid (30.0 mg, 0.14 mmol) in Pyridine (0.5 mL) were added EDCI (27.6 mg,0.14 mmol) and(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (26.0 mg, 0.14 mmol). The suspension was stirred at 20° C.for 16 hr. The reaction mixture was quenched with H₂O (10 mL). Theresidue was diluted with EtOAc (20 mL×3), washed with saturated NaCl (5mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum.The solution was purified by prep-HPLC (NH₃) and lyophilized to affordthe title compound (1.88 mg, 3.5% yield) as white solid.

LC-MS Method1: 3.486 min, MS (m/z): 371.3 (M+H⁺).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=1.25 Hz, 1H), 7.36 (s,1H), 4.70 (br d, J=12.30 Hz, 1H), 4.12 (d, J=12.30 Hz, 1H), 3.87 (br d,J=12.30 Hz, 1H), 3.79 (dd, J=9.41, 6.65 Hz, 1H), 3.54 (br d, J=8.53 Hz,1H), 2.57 (s, 2H), 1.80-2.10 (m, 4H), 1.51-1.60 (m, 2H), 1.41 (br d,J=6.78 Hz, 9H), 1.30 (s, 7H), 1.18 (s, 7H).

Example 20[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazol-4-yl}methanone(R)-2-methyl-N—[(E)-tetrahydro-2H-pyran-4-ylmethylene]-2-propanesulfinamide

A 100 mL round-bottom flask was charged withtetrahydro-2H-pyran-4-carbaldehyde (5000 mg, 43.81 mmol),(R)-2-methylpropane-2-sulfinamide (5309.27 mg, 43.81 mmol), Ti(OEt)₄(13.5 mL, 65.71 mmol) and THF (25 mL). The reaction was heated at 60° C.for 30 min under N₂ protection to give a yellow solution. TLC(PE/EA=3/1, Rf=0.4) showed a new spot was detected. H₂O (3 mL) was addeddropwise and it was stirred at 20° C. for 5 mins, then it was filtratedthrough a pad of celite and the filtrate concentrated in vacuum to givethe title compound (8700 mg, 40.031 mmol, 91.383% yield) as white solid.

LC-MS Method1 0.745 min, MS (m/z) 218.1 (M+H⁺).

(R)-2-methyl-N-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-2-propanesulfinamide

A round-bottom flask charged with(R)-2-methyl-N—[(E)-tetrahydro-2H-pyran-4-ylmethylene]-2-propanesulfinamide(3000 mg, 13.8 mmol) and THF (30 mL) was cooled to −48° C., MeMgBr (5.06mL, 15.18 mmol) was added dropwise to the mixture. The reaction wasstirred at this temperature for 2 hr to give a yellow solution. H₂O (30mL) was added and it was extracted with EtOAc (30 mL×2). The combinedorganic layer dried over Na₂SO₄ and concentrated in vacuum to give ayellow oil. The crude was purified by silica gel chromatography(DCM/EA=3/1 to 1/1) to give the title compound (1700 mg, 7.2846 mmol,52.772% yield) as colorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.05-3.95 (m, 2H), 3.40 (dt, J=4.0,1.6 Hz, 2H), 3.25-3.10 (m, 1H), 2.90 (d, J=7.6 Hz, 1H), 1.85-1.75 (m,1H), 1.70-1.20 (m, 4H), 1.29 (d, J=6.8 Hz, 3H), 1.25 (s, 9H).(1S)-1-(tetrahydro-2H-pyran-4-yl)ethanamine hydrochloride

A 100 ml round-bottom flask was charged with(R)-2-methyl-N-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-2-propanesulfinamide(1700 mg, 7.28 mmol) and HCl/MeOH (10 mL, 7.28 mmol). The reactionmixture was stirred at 25° C. for 3 hr to give a colorless oil. It wasevaporated in vacuum to give the title compound (1250 mg, 7.5456 mmol,103.58% yield) as colorless oil.

ethyl1-[(15)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazole-4-carboxylate

A microwave tube was charged with ethyl(2Z)-3-(dimethylamino)-2-isocyanoacrylate (400.29 mg, 2.38 mmol),(1S)-1-(tetrahydro-2H-pyran-4-yl)ethanamine hydrochloride (394.27 mg,2.38 mmol), triethylamine (0.5 mL, 3.57 mmol) and 1-Butanol (0.6004 mL).It was irradiated with microwave at 130° C. for 1 hr to give a brownsolution. H₂O (15 mL) was added and it was extracted with EtOAc (15mL×2). The combined organic layer dried over Na₂SO₄ and concentrated invacuum to give a yellow oil. The crude was purified by silica gelchromatography (PE/EA=1/1 to 0/1) to give the title compound (135 mg,0.5351 mmol, 22.481% yield) as as yellow oil.

LC-MS Method1 0.638, MS (m/z) 253.2 (M+H⁺).

1-[(S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazole-4-carboxylic acid

A 100 mL round-bottom flask was charged with ethyl1-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazole-4-carboxylate(130 mg, 0.5200 mmol), hydroxylithium hydrate (43.24 mg, 1.03 mmol), THF(3 mL). It was stirred at 20° C. for 3 hr to give a yellow solution. H₂O(15 mL) was added and it was extracted with EtOAc (15 mL×2). The aqueousphase was lyophilized to give the title compound (110 mg, 0.4905 mmol,95.199% yield) as yellow solid. It was directly used in the next step.

[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazol-4-yl}methanone

To a mixture of1-[(1S)-1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazole-4-carboxylicacid (110 mg, 0.4900 mmol) and HATU (243.77 mg, 0.6400 mmol) in DMF (5mL) was added N-ethyl-N-isopropylpropan-2-amine (0.59 mL, 3.43 mmol).After stirred for 30 min,(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (384.3 mg, 0.7400 mmol) was added. The reaction mixturewas stirred for another 16 hr to give a yellow solution. H₂O (30 mL) wasadded and it was extracted with EtOAc (30 mL×2). The combined organiclayer dried over Na₂SO₄ and concentrated in vacuum to give a yellow oil.The crude was purified by Prep-HPLC (NH₃). The afforded flows wereconcentrated in vacuum to remove most of CH₃CN and lyophilized to givethe title compound (9.57 mg, 0.0248 mmol, 5.0482% yield) as white solid.

LC-MS Method1: 387.3 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12-1.17 (m, 1H) 1.23 (dd,J=12.30, 4.02 Hz, 1H) 1.37 (s, 6H) 1.46 (br d, J=3.01 Hz, 1H) 1.50 (d,J=6.78 Hz, 3H) 1.68 (br d, J=13.05 Hz, 1H) 1.78 (br d, J=8.78 Hz, 1H)1.94-1.99 (m, 1H) 2.04-2.11 (m, 1H) 2.63 (s, 2H) 3.25 (td, J=11.80, 2.26Hz, 1H) 3.36 (td, J=11.92, 2.01 Hz, 1H) 3.61 (dd, J=12.42, 3.89 Hz, 1H)3.81-3.88 (m, 1H) 3.92 (br t, J=11.80 Hz, 2H) 4.02 (br dd, J=1 1.54,3.76 Hz, 1H) 4.18 (br d, J=13.05 Hz, 1H) 4.75 (dd, J=12.05, 4.27 Hz, 1H)7.40 (s, 1H) 7.62 (s, 1H)

Example 21[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-phenylethyl]-1H-imidazol-4-yl}methanoneethyl 1-[(1)-1-phenylethyl]-1H-imidazole-4-carboxylate

A mixture of ethyl isocyanoacetate (1.0 g, 8.84 mmol) and1,1-dimethoxy-N,N-dimethylmethanamine (1.53 mL, 11.49 mmol) was stirredat 0° C. for 3 h. TLC (PE:EA=3:1) showed ethyl 2-isocyanoacetate (1.g,8.84 mmol) (Rf=0.6) was consumed completely and new spot (Rf=0.4) wasdetected. (S)-1-phenylethanamine (4.5 mL, 35.36 mmol) was added to themixture. The obtained mixture was stirred at 50° C. for 16 h to givebrown mixture. TLC (PE:EA=1:1) showed new spot (Rf=0.1) was detected.The mixture was concentrated to give a residue. The residue was purifiedby flash column (PE:EA=1:0 to 0:1) to afford the title compound (0.9300g, 3.807 mmol, 43.06% yield)(PE:EA=1:1, Rf=0.1) as a brown oil.

LC-MS Method1 0.685 min, MS (m/z) 244.9 (M+H⁺).

1-[(1S)-1-phenylethyl]-1H-imidazole-4-carboxylic acid

To a mixture of ethyl 1-[(1S)-1-phenylethyl]-1H-imidazole-4-carboxylate(930 mg, 3.81 mmol) in THF (6 mL) and H₂O (3 mL) was added LiOH.H₂O(0.33 mL, 5.71 mmol). The reaction mixture was stirred at 20° C. for 16h to give yellow mixture. TLC (PE:EtOAc=1:1) showed the startingmaterial was consumed completely. The reaction mixture was diluted withH₂O (15 mL) and extracted with EtOAc (8 mL×5). The aqueous phase wasacidified with 1 N HCl aq. to pH=4. The resulting aqueous phase wasdried in vacuum to afford the title compound (900 mg, 4.162 mmol,109.33% yield) (crude) as brown solid.

LC-MS Method1 0.539 min, MS (m/z) 216.9 (M+H⁺).

[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-phenylethyl]-1H-imidazol-4-yl}methanone

To a mixture of(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (100 mg, 0.5500 mmol) in DMF (2 mL) were added1-[(1S)-1-phenylethyl]-1H-imidazole-4-carboxylic acid (143.96 mg, 0.6700mmol), DIPEA (0.37 mL, 2.22 mmol) and HATU (254.51 mg, 0.6700 mmol). Thereaction mixture was stirred at 25° C. for 16 h to give brown mixture.TLC (DCM:MeOH=40:1, a drop of Et₃N) showed one new spot (Rf=0.5) wasdetected. The reaction mixture was diluted with H₂O (10 mL). Theresulting mixture was extracted with EtOAc (5 mL×4). The combinedorganic phase was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to give a residue. The residue was purified by prep-TLC(DCM:MeOH=40:1, 1% Et₃N in the solvent) to give crude product. The crudeproduct was purified by prep-HPLC (NH₃). The afforded flows werecombined, concentrated to remove most of CH₃CN and lyophilized to affordthe title compound (3.85 mg, 0.0102 mmol, 1.8336% yield) as white solid.

LC-MS Method1: 379.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.67 (br s, 1H), 7.48 (s, 1H),7.31-7.40 (m, 3H), 7.18 (br d, J=6.5 Hz, 2H), 5.35 (q, J=6.9 Hz, 1H),4.75 (br d, J=8.0 Hz, 1H), 4.18 (br d, J=12.3 Hz, 1H), 3.88-4.01 (m,1H), 3.61 (br d, J=8.8 Hz, 1H), 2.64 (s, 2H), 2.07 (br s, 1H), 1.98 (brs, 1H), 1.88 (d, J=7.0 Hz, 3H), 1.46 (br s, 1H), 1.38 (s, 6H), 1.26 (s,1H)

Example222-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}-1H-imidazol-1-yl)ethyl]benzonitrile(R)—N—[(E)-(2-bromophenyl)methylene]-2-methyl-2-propanesulfinamide

A 100 mL round-bottom flask was charged with 2-bromobenzaldehyde (2000mg, 10.81 mmol), (R)-2-methylpropane-2-sulfinamide (1310.13 mg, 10.81mmol), Ti(OEt)₄ (3.33 mL, 16.21 mmol) and THF (9.2536 mL). The reactionwas heated at 60° C. for 30 min under N2 protection to give a yellowsolution. TLC (PE/EA=3/1, Rf=0.4) showed a new spot was detected. H₂O (3mL) was added dropwise and it was stirred at 20° C. for 5 min, then itwas filtrate through a pad of celite and concentrated in vacuum to givethe title compound (3050 mg, 10.583 mmol, 97.903% yield) as white solid.

(R)—N-[(1S)-1-(2-bromophenyl)ethyl]-2-methyl-2-propanesulfinamide

A round-bottom flask charged with(R)—N—[(E)-(2-bromophenyl)methylene]-2-methyl-2-propanesulfinamide (3000mg, 10.41 mmol) and THF (25 mL) was cooled to −48° C., andchloro(methyl)magnesium (4.16 mL, 12.49 mmol) was added dropwise to themixture. The reaction was stirred at this temperature for 2 hr to give ayellow solution. H₂O (30 mL) was added and it was extracted with EtOAc(30 mL×2). The combined organic layer was dried over Na₂SO₄ andconcentrated in vacuum to give a yellow oil. The crude was purified bysilica gel chromatography (DCM/EA=10/1 to 3/1) to give the titlecompound (960 mg, 3.1553 mmol, 30.312% yield) as white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.54 (d, J=8.0 Hz, 1H), 7.43 (dd,J=8.0, 0.8 Hz, 1H), 7.40-7.20 (m, 1H), 7.20-7.10 (m, 1H), 5.05-4.95 (m,1H), 3.37 (d, J=4.0 Hz, 1H), 1.54 (d, J=6.8 Hz, 3H), 1.21 (s, 9H).(1S)-1-(2-bromophenyl)ethanamine hydrochloride

A solution of(R)—N-[(1S)-1-(2-bromophenyl)ethyl]-2-methyl-2-propanesulfinamide (900mg, 2.96 mmol) in HCl/MeOH (105.31 mg, 2.96 mmol) was stirred at 30° C.for 16 hr to give a colorless solution. The reaction mixture wasevaporated in vacuum to give the title compound (700 mg, 2.95 mmol,100.04% yield) as yellow oil. It was used directly in the next step.

LC-MS Method1 0.592 min, MS (m/z) 202.1 (M+H⁺).

ethyl 1-[(1S)-1-(2-bromophenyl)ethyl]-1H-imidazole-4-carboxylate

A 8 mL microwave vial was charged with (1S)-1-(2-bromophenyl)ethanaminehydrochloride (780 mg, 3.3 mmol), ethyl(2Z)-3-(dimethylamino)-2-isocyanoacrylate (554.61 mg, 3.3 mmol), Et₃N(0.69 mL, 4.95 mmol) and 1-Butanol (3 mL). The reaction was irradiatedwith microwave at 130° C. for 1 h to give a brown red solution. Thereaction mixture was diluted with saturated Na₂CO₃ aq. (10 mL) andextracted with EtOAc (20 mL×2). The combined organic layer dried overNa₂SO₄ and concentrated in vacuum to give a yellow oil. The crude waspurified by silica gel chromatography (DCM/EA=10/1 to 6/1) to give thetitle compound (230 mg, 0.7117 mmol, 21.581% yield) as yellow oil.

LC-MS Method1 0.726 min, MS (m/z) 324.9 (M+H⁺).

ethyl 1-[(1S)-1-(2-cyanophenylethyl]-1H-imidazole-4-carboxylate

A 50 mL round-bottom flask was charged with ethyl1-[(1S)-1-(2-bromophenyl)ethyl]-1H-imidazole-4-carboxylate (180 mg,0.5600 mmol), Zn(CN)₂ (130.78 mg, 1.11 mmol), Pd₂(dba)₃ (25.5 mg, 0.0300mmol), P(t-Bu)₃.HBF₄ (32.32 mg, 0.1100 mmol), Zn (14.57 mg, 0.2200 mmol)and DMF (2 mL). The reaction mixture was stirred at 120° C. for 16 h togive a yellow solution. H₂O (15 mL) was added and it was extracted withEtOAc (20 mL×2). The combined organic layer dried over Na₂SO₄ andconcentrated in vacuum to give a yellow oil. The reaction mixture wasevaporated in vacuum to give the title compound (60 mg, 0.2228 mmol,40.004% yield) as yellow oil. It was used directly in the next step.

1-[(1S)-1-(2-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid

To a mixture of ethyl1-[(1S)-1-(2-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate (150 mg,0.5600 mmol) in 1,4-Dioxane (5 mL) was added a solution of LiOH.H₂O(46.74 mg, 1.11 mmol) in H₂O (1.5 mL, 0.5600 mmol). It was reacted at20° C. for 16 h to give a yellow solution. The reaction mixture wasevaporated in vacuum to give the title compound (160 mg, 0.6632 mmol,119.07% yield) as white solid.

LC-MS Method1 0.688 min, MS (m/z) 242.2 (M+H⁺).

2-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}-1H-imidazol-1-yl)ethyl]benzonitrile

To a solution of1-[(1S)-1-(2-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid (50 mg,0.2100 mmol) in DMF (2 mL) were added N-ethyl-N-isopropylpropan-2-amine(0.18 mL, 1.04 mmol) and HATU (118.85 mg, 0.3100 mmol) at 20° C. Afterstirred for 30 min,(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (52.47 mg, 0.21 mmol) was added and stirred for 16 hr togive black suspension. H₂O (30 mL) was added and it was extracted withEtOAc (30 mL×2). The combined organic layer dried over Na₂SO₄ andconcentrated in vacuum to give a yellow oil. The crude was purified byPrep-HPLC (NH₃). The afforded flows were concentrated in vacuum toremove most of CH₃CN and lyophilized to give the title compound (37.35mg, 0.0926 mmol) as white solid.

LC-MS Method1: 404.3 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.70 (dd, J=1.00, 7.53 Hz, 1H), 7.67(d, J=1.51 Hz, 1H), 7.56-7.63 (m, 2H), 7.41-7.48 (m, 1H), 7.20 (d,J=8.03 Hz, 1H), 5.78 (q, J=7.03 Hz, 1H), 4.73 (dd, J=2.89, 12.17 Hz,1H), 4.16 (d, J=12.55 Hz, 1H), 3.93 (br d, J=10.29 Hz, 1H), 3.60 (dd,J=4.14, 12.42 Hz, 1H), 2.63 (d, J=2.26 Hz, 2H), 2.07 (br d, J=3.51 Hz,1H), 1.95-1.99 (m, 1H), 1.94 (d, J=7.03 Hz, 3H), 1.45 (br d, J=3.26 Hz,1H), 1.36 (s, 6H)

Example233-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}-1H-imidazol-1-yl)ethyl]benzonitrile(R)—N—[(E)-(3-cyanophenyl)methylene]-2-methyl-2-propanesulfinamide

To a solution of (R)-2-methylpropane-2-sulfinamide (4621.37 mg, 38.13mmol) in THE (20 mL) were added 3-formylbenzonitrile (5000 mg, 38.13mmol) and tetraethoxytitanium (11.86 mL, 57.2 mmol) at 60° C. Theresulting mixture was stirred at 60° C. for 0.5 hours to give yellowsolution. H₂O (3 mL) was added dropwise and it was stirred for 5 min.Then solid was filtered through a pad of celite and the filtrate wasconcentrated in vacuum to afford the title compound (7630 mg, 32.562mmol, 85.398% yield) as white solid. It was used directly for the nextstep without further purification.

LC-MS Method1 0.858 min, MS (m/z) 235.2 (M+H⁺).

(R)—N-[(1S)-1-(3-cyanophenyl)ethyl]-2-methyl-2-propanesulfinamide

To a solution of(R)—N—[(E)-(3-cyanophenyl)methylene]-2-methyl-2-propanesulfinamide (3000mg, 12.8 mmol) in THE (32.054 mL) was added chloro(methyl)magnesium(4.69 mL, 14.08 mmol) at −48° C. The resulting mixture was stirred at−40° C. for 14 hours to give yellow solution. The reaction mixture waspoured into sat. NH₄C1 aq. (30 mL) and extracted with EtOAc (30 mL×4).The combined organic layers were washed with brine (30 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thetitle compound (960 mg, 3.8345 mmol, 29.95% yield) as yellow solid.

LC-MS Method1 0.845 min, MS (m/z) 251.2 (M+H⁺).

3-[(1S)-1-aminoethyl]benzonitrile hydrochloride

To (R)—N-[(1S)-1-(3-cyanophenyl)ethyl]-2-methyl-2-propanesulfinamide(960 mg, 3.83 mmol) was added HCl/MeOH (10 mL, 3.83 mmol) at 20° C. Theresulting mixture was stirred at 20-25° C. for 0.5 hours to give yellowsolution. The reaction mixture was evaporated in vacuum to give thetitle compound (643 mg, crude product) as yellow oil.

LC-MS Method1 0.258 min, MS (m/z) 147. (M−HCl+H+).

ethyl 1-[(1S)-1-(3-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate

To a solution of 3-[(1S)-1-aminoethyl]benzonitrile hydrochloride (250mg, 1.49 mmol) in 1-Butanol (2.5 mL) were added Et₃N (0.31 mL, 2.23mmol) and ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (271.49 mg,1.49 mmol) The reaction mixture was irradiated with microwave at 130° C.for 60 min to give a yellow solution. The reaction mixture was pouredinto sat. NH₄Cl aq. (30 mL) and extracted with EtOAc (30 mL×2). Thecombined organic layers were washed with brine (30 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thetitle compound (90 mg, 0.3342 mmol, 22.484% yield) as yellow oil.

LC-MS Method1 0.732 min, MS (m/z) 270.2 (M+H⁺).

1-[(1S)-1-(3-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid

To a solution of ethyl1-[(1S)-1-(3-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate (90 mg,0.3300 mmol) was added hydroxylithium hydrate (28.05 mg, 0.6700 mmol) inTHF (0.90 mL), H₂O (0.90 mL) and MeOH (0.90 mL) at 20° C. The resultingmixture was stirred at 20-25° C. for 14 hours to give yellow solution.The reaction mixture was poured into H₂O and extracted with EtOAc (20mL×4). The aqueous layers were concentrated and lyophilized to affordthe title compound (132 mg, crude product) as white solid.

LC-MS Method1 0.468 min, MS (m/z) 241.9 (M+H⁺).

3-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}-1H-imidazol-1-yl)ethyl]benzonitrile

To a solution of1-[(1S)-1-(3-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid (60 mg,0.2500 mmol) in DMF (1.8 mL) were added HATU (123.6 mg, 0.3200 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.3 mL, 1.74 mmol) at 20° C. Thereaction mixture was stirred at 20° C. for 30 min. Then(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (62.96 mg, 0.2500 mmol) was added. The resulting mixturewas stirred at 20-25° C. for 14 hours to give yellow solution. Thereaction mixture was poured into sat. NH₄Cl aq. (80 mL) and extractedwith EtOAc (50 mL×4). The combined organic layers were washed with sat.aq. (50 mL×2), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by prep-HPLC (FA) to thetitle compound (10 mg, 0.0248 mmol, 9.9654% yield) as white solid.

LC-MS Method1: 404.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.63 (br d, J=7.8 Hz, 2H), 7.52-7.46(m, 2H), 7.44 (s, 1H), 7.37 (br d, J=8.0 Hz, 1H), 5.40 (q, J=6.9 Hz,1H), 4.73 (br d, J=12.3 Hz, 1H), 4.17 (br d, J=12.3 Hz, 1H), 3.98-3.91(m, 1H), 3.64-3.58 (m, 1H), 2.64 (s, 2H), 2.08 (br s, 1H), 1.98 (br d,J=3.3 Hz, 1H), 1.90 (d, J=7.0 Hz, 3H), 1.46 (t, J=3.3 Hz, 1H), 1.36 (s,6H)

Example244-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}-1H-imidazol-1-yl)ethyl]benzonitrile(R)—N—[(E)-(4-cyanophenyl)methylene]-2-methyl-2-propanesulfinamide

To a solution of (R)-2-methylpropane-2-sulfinamide (4621.37 mg, 38.13mmol) in THF (20 mL) were added 4-formylbenzonitrile (5000 mg, 38.13mmol) and tetraethoxytitanium (13.05 g, 57.2 mmol) at 60° C. Theresulting mixture was stirred at 60° C. for 0.5 hours to give yellowsolution. H₂O (3 mL) was added dropwise and it was stirred for 5 mins.Then the solid was removed by filtration through a pad of celite and thefiltrate was concentrated in vacuum to give the title compound (8340 mg,35.592 mmol, 93.345% yield) as white solid.

LC-MS Method1 0.858 min, MS (m/z) 234.8 (M+H⁺).

(R)—N-[(1S)-1-(4-cyanophenyl)ethyl]-2-methyl-2-propanesulfinamide

To a solution of(R)—N—[(E)-(4-cyanophenyl)methylene]-2-methyl-2-propanesulfinamide (2340mg, 9.99 mmol) in THF (30 mL) was added chloro(methyl)magnesium (4.99mL, 14.98 mmol) at −48° C. The resulting mixture was stirred at −40° C.for 14 hours to give yellow solution. The mixture was quenched withNH₄C1 and the aqueous layer was extracted with EA (30 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andthen concentrated in vacuum. The crude product was purified by silicacolumn (PE to PE:EtOAc=1:1). The afforded solid was triturated withEtOAc/hexane (20 mL/10 mL) and dried in air to give the title compound(1310 mg, 5.2325 mmol, 52.396% yield) as yellow solid.

LC-MS Method1 0.732 min, MS (m/z) 250.9 (M+H⁺).

4-[(1S)-1-aminoethyl]benzonitrile hydrochloride

To (R)—N-[(1S)-1-(4-cyanophenyl)ethyl]-2-methyl-2-propanesulfinamide(1310 mg, 5.23 mmol) was added HCl/MeOH (10 mL, 5.23 mmol) at 20° C. Theresulting mixture was stirred at 20-25° C. for 0.5 hours to give yellowsolution. The reaction mixture was evaporated in vacuum to give thetitle compound (1 g, crude product) as a yellow oil.

LC-MS Method1 0.302 min, MS (m/z) 146.8 (M+H⁺).

ethyl 1-[(1S)-1-(4-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate

To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (300mg, 1.78 mmol) in 1-Butanol (3 mL) were added Et₃N (0.38 mL, 2.68 mmol)and 4-[(1S)-1-aminoethyl]benzonitrile hydrochloride (300 mg, 1.78 mmol).The reaction mixture was irradiated with microwave at 130° C. for 60 minto give a yellow solution. The reaction mixture was poured into sat.NH₄Cl aq. (30 mL) and extracted with EtOAc (30 mL×2). The combinedorganic layers were washed with sat. aq. (30 mL×2), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the titlecompound (110 mg, 0.4085 mmol, 22.9% yield) as yellow oil.

LC-MS Method1 0.732 min, MS (m/z) 270.2 (M+H⁺).

1-[(1S)-1-(4-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid

To a solution of ethyl1-[(1S)-1-(4-cyanophenyl)ethyl]-1H-imidazole-4-carboxylate (110 mg,0.4100 mmol) in THF (1.1 mL), H₂O (1.1 mL) and MeOH (0.1 mL) was addedhydroxylithium hydrate (34.28 mg, 0.8200 mmol) at 20° C. The resultingmixture was stirred at 20-25° C. for 14 hours to give yellow solution.The reaction mixture was poured into H₂O and extracted with EtOAc (20mL×4). The aqueous layer was concentrated and lyophilized to afford thetitle compound (130 mg, crude product) as yellow solid.

LC-MS Method1 0.443 min, MS (m/z) 241.9 (M+H⁺).

4-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}-1H-imidazol-1-yl)ethyl]benzonitrile

To a solution of1-[(1S)-1-(4-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid (100 mg,0.4100 mmol) in DMF (3 mL) were added HATU (206.01 mg, 0.5400 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.5 mL, 2.9 mmol) at 20° C. Thereaction mixture was stirred for 30 min. Then(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (104.94 mg, 0.4100 mmol) was added. The resulting mixturewas stirred at 20-25° C. for 14 hours to give yellow solution. Thereaction mixture was poured into sat. NH₄Cl aq. (20 mL) and extractedwith EtOAc (20 mL×3). The crude product was purified by Prep-HPLC (FA)to give the title compound (2 mg, 0.0050 mmol, 1.1958% yield) as yellowsolid.

LC-MS Method1: 404.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.66 (br d, J=8.0 Hz, 3H), 7.51 (br d,J=9.0 Hz, 1H), 7.23 (br s, 2H), 5.42 (br d, J=7.0 Hz, 1H), 4.72 (br s,1H), 4.17 (br d, J=12.8 Hz, 1H), 3.93 (br d, J=12.0 Hz, 1H), 3.61 (br d,J=14.8 Hz, 1H), 2.63 (s, 2H), 2.08 (br s, 1H), 1.98 (br s, 1H), 1.90 (brd, J=7.0 Hz, 3H), 1.47 (br s, 1H), 1.37 (s, 6H)

Example 25[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(2-pyridinyl)ethyl]-1H-imidazol-4-yl}methanoneethyl 1-[(1S)-1-(2-pyridinyl)ethyl]-1H-imidazole-4-carboxylate

The mixture of (1S)-1-(2-pyridinyl)ethanamine (500 mg, 4.09 mmol) andethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (137.67 mg, 0.8200 mmol)was stirred at 50° C. for 16 h. The reaction mixture was concentrateddirectly. The residue was purified by prep-TLC (PE:EtOAc=0:1) to givethe title compound as brown oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.61 (d, J=4.0 Hz, 1H), 7.78 (d, J=1.2Hz, 1H), 7.70-7.60 (m, 2H), 7.30-7.20 (m, 1H), 7.02 (d, J=8.0 Hz, 1H),5.50-5.35 (m, 1H), 4.36 (q, J=6.8 Hz, 2H), 1.94 (d, J=7.6 Hz, 3H), 1.38(t, J=6.8 Hz, 3H).1-[(1S)-1-(2-pyridinyl)ethyl]-1H-imidazole-4-carboxylic acid

To a solution of ethyl1-[(1S)-1-(2-pyridinyl)ethyl]-1H-imidazole-4-carboxylate (160 mg, 0.6500mmol) in THF (5 mL) and H₂O (1 mL, 55.56 mmol) was added LiOH.H₂O (0.11mL, 1.96 mmol). The mixture was stirred at 20° C. for 12 h to give brownsuspension. LCMS showed the starting material consumed up. The reactionmixture was concentrated. The afforded H₂O layer was acidified with 1 NHCl aq. to pH=5-7 and lyophilized to give the title compound (130 mg,0.5985 mmol, 91.746% yield) as white solid.

[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(2-pyridinyl)ethyl]-1H-imidazol-4-yl}methanone

To a solution of 1-[(1S)-1-(2-pyridinyl)ethyl]-1H-imidazole-4-carboxylicacid (130 mg, 0.6000 mmol) in DMF (2 mL) were added HATU (274.55 mg,0.7200 mmol), DIPEA (0.49 mL, 2.99 mmol),(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (108 mg, 0.6000 mmol). The mixture was stirred at 30° C.for 3 h to give brown solution. The reaction mixture was concentrateddirectly. The residue was purified by prep-HPLC (NH₃) and the affordedflows were combined, concentrated to remove most of CH₃CN andlyophilized to give the title compound (48.15 mg, 0.1269 mmol, 21.202%yield) as light yellow solid.

LC-MS Method1: 380.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.60 (1H, d, J=4.63 Hz), 7.74 (1H,br d, J=2.38 Hz), 7.67 (1H, td, J=7.75, 1.50 Hz), 7.60 (1H, s), 7.24(1H, dd, J=7.44, 4.82 Hz), 7.03 (1H, d, J=7.88 Hz), 5.43 (1H, q, J=7.00Hz), 4.74 (1H, dd, J=12.07, 3.69 Hz), 4.18 (1H, d, J=12.51 Hz),3.90-4.01 (1H, m), 3.61 (1H, dd, J=12.51, 4.13 Hz), 2.64 (2H, s), 2.07(1H, br d, J=3.38 Hz), 1.97 (1H, br dd, J=7.13, 3.50 Hz), 1.92 (3H, d,J=7.00 Hz), 1.45 (1H, t, J=3.31 Hz), 1.31-1.43 (6H, m)

Example 26[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(4-pyridinyl)ethyl]-1H-imidazol-4-yl}methanone(1R)-1-(4-pyridinyl)ethyl 4-methylbenzenesulfonate

To a solution of (1R)-1-(4-pyridinyl)ethanol in THF (5 mL) was added NaH(148.11 mg, 6.17 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5h. 4-methylbenzene-1-sulfonyl chloride (0.29 mL, 1.95 mmol) was addedand the mixture was stirred at 20-25° C. for 16 h. The reaction mixturewas poured into H₂O (10 mL) and extracted with EtOAc (10 mL×4). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified byflash column (PE to 30% EtOAc in PE) to afford the title compound (330mg, 1.1899 mmol, 73.267% yield) as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.54-8.48 (m, 2H), 7.69 (d, J=8.5 Hz,2H), 7.25 (d, J=8.0 Hz, 2H), 7.13-7.10 (m, 2H), 5.54 (q, J=6.6 Hz, 1H),2.42 (s, 3H), 1.59 (d, J=6.8 Hz, 3H) ethyl1-[(1S)-1-(4-pyridinyl)ethyl]-1H-imidazole-4-carboxylate

To a solution of (1R)-1-(4-pyridinyl)ethyl 4-methylbenzenesulfonate (280mg, 1.01 mmol) in DMF (11.2 mL) were added methyl1H-imidazole-5-carboxylate (127.32 mg, 1.01 mmol) and Cs₂CO₃ (164.47 mg,0.50 mmol). The mixture was stirred at 40° C. for 16 h. The reactionmixture was poured into H₂O (10 mL) and extracted with EtOAc (15 mL×4).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-TLC (DCM:MeOH=10:1) to afford the title compound (28 mg, 0.1211mmol, 11.993% yield) as a yellow oil.

LC-MS Method1: 232.1 [M+H]+ ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.64-8.60(m, 2H), 7.68-7.59 (m, 2H), 7.05-7.01 (m, 2H), 5.39 (q, J=7.0 Hz, 1H),3.95-3.84 (m, 3H), 1.91 (d, J=7.3 Hz, 3H)1-[(1S)-1-(4-pyridinyl)ethyl]-1H-imidazole-4-carboxylic acid

To a solution of ethyl1-[(1S)-1-(4-pyridinyl)ethyl]-1H-imidazole-4-carboxylate (50 mg, 0.22mmol) in THF (2 mL) and H₂O (1 mL) was added LiOH.H₂O (13.61 mg, 0.32mmol). The mixture was stirred at 20-25° C. for 2 h. The reactionmixture was concentrated directly. The reaction mixture was acidifiedwith 1 N HCl aq. to pH=6 and then lyophilized to afford the titlecompound (40 mg, 0.1841 mmol, 85.167% yield) as a yellow oil.

1H NMR (400 MHz, DMSO-d₆) δ=8.59-8.50 (m, 21H), 7.95 (s, 1H), 7.83 (s,1H), 7.25 (d, J=6.3 Hz, 2H), 5.66 (q, J=7.1 Hz, 1H), 1.81 (d, J=7.3 Hz,3H)[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(4-pyridinyl)ethyl]-1H-imidazol-4-yl}methanone

To a solution of 1-[(LS)-1-(4-pyridinyl)ethyl]-1H-imidazole-4-carboxylicacid (20 mg, 0.09 mmol) in Pyridine (1 mL) were added EDCI (26.48 mg,0.14 mmol) and(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (19.95 mg, 0.0900 mmol). The resulting mixture was stirredat 20-25° C. for 16 h. The reaction mixture was concentrated directly.The residue was purified by prep-HPLC (NH₃). The afforded flows werecombined, concentrated to remove most of CH₃CN and lyophilized to affordthe title compound (24.99 mg, 0.0659 mmol, 71.527% yield) as a yellowsolid.

LC-MS Method1: 380.1 [M+H]⁺

1H NMR (400 MHz, CHLOROFORM-d) δ=8.61 (d, J=5.8 Hz, 21H), 7.68 (s, 1H),7.51 (s, 1H), 7.03 (d, J=5.8 Hz, 2H), 5.36 (q, J=6.9 Hz, 1H), 4.76 (dd,J=2.9, 12.2 Hz, 1H), 4.19 (br d, J=12.3 Hz, 1H), 4.02-3.89 (m, 1H), 3.62(dd, J=4.1, 12.7 Hz, 1H), 2.64 (s, 2H), 2.13-1.96 (m, 2H), 1.90 (d,J=7.3 Hz, 3H), 1.48 (t, J=3.4 Hz, 1H), 1.38 (s, 6H)

Example 27[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(1,3-thiazol-2-yl)ethyl]-1H-imidazol-4-yl}methanoneethyl 1-[(1S)-1-(1,3-thiazol-2-yl)ethyl]-1H-imidazole-4-carboxylate

To a solution of (1S)-1-(1,3-thiazol-2-yl)ethanamine (131.19 mg, 0.7800mmol) in 1-Butanol (1.4 mL) were added ethyl(2Z)-3-(dimethylamino)-2-isocyanoacrylate (100 mg, 0.7800 mmol) and Et₃N(0.16 mL, 1.17 mmol) at 25° C. The resulting mixture was subjected toreaction in microwave reactor (time: 1 h, temp: 130° C.). The reactionmixture was poured into H₂O (5 mL) and extracted with EA (5 mL×3). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give a crudeproduct. The crude product was purified by Prep-TLC (EA) to give thetitle compound (50 mg, 0.1990 mmol, 25.507% yield) as a yellow oil.

1-[(1S)-1-(1,3-thiazol-2-yl)ethyl]-1H-imidazole-4-carboxylic acid

To a solution of ethyl1-[(1S)-1-(1,3-thiazol-2-yl)ethyl]-1H-imidazole-4-carboxylate (50 mg,0.2000 mmol) in THF (3 mL) and H₂O (1 mL) was added LiOH.H₂O (41.75 mg,0.9900 mmol). The reaction mixture was stirred at 25° C. for 16 hours togive a yellow mixture. The reaction mixture was concentrated in vacuumto remove most of THF. The residue was diluted with H₂O (5 mL) andacidified with 0.5 M HCl aq. to pH=6. Then the solution was lyophilizedto give the title compound as a yellow solid.

[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(1,3-thiazol-2-yl)ethyl]-1H-imidazol-4-yl}methanone

To a solution of1-[(1S)-1-(1,3-thiazol-2-yl)ethyl]-1H-imidazole-4-carboxylic acid (44mg, 0.2000 mmol) in Pyridine (2 mL) was added EDCI (56.67 mg, 0.3000mmol). The mixture was stirred at 25° C. under N₂ for 10 min. Then(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (42.71 mg, 0.2000 mmol) was added. The resulting mixturewas stirred at 25° C. for 2 hours to give a yellow solution. Thereaction mixture was poured into H₂O (5 mL) and extracted with EA (5mL×3). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The crude product was purified by Prep-HPLC (NH₃) to give thetitle compound (60 mg, 0.1557 mmol, 78.975% yield) as a white solid.

LC-MS Method1: 386.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.79 (d, J=3.3 Hz, 1H), 7.75 (s, 1H),7.62 (s, 1H), 7.35 (d, J=3.3 Hz, 1H), 5.70 (q, J=6.9 Hz, 1H), 4.73 (dd,J=8.8, 11.9 Hz, 1H), 4.18 (br d, J=12.3 Hz, 1H), 3.99-3.91 (m, 1H), 3.61(dd, J=4.2, 12.7 Hz, 1H), 2.64 (s, 2H), 2.11-2.06 (m, 1H), 2.03 (d,J=7.0 Hz, 3H), 2.00-1.95 (m, 1H), 1.37 (s, 6H)

Example 28[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-1H-imidazol-4-yl}methanone(R)-2-methyl-N—[(E)-1,3-thiazol-5-ylmethylene]-2-propanesulfinamide

To a mixture of 5-formylthiazole (2.14 mL, 17.68 mmol) in THF (20 mL)were added (R)-2-methylpropane-2-sulfinamide (2142.48 mg, 17.68 mmol)and Ti(OEt)₄ (6045.61 mg, 26.52 mmol). The reaction mixture was stirredat 60° C. for 2 h to give yellow mixture. TLC (PE:EtOAc=2:1) showed thestarting material was consumed completely, and one new spot was (Rf=0.5)detected. The reaction mixture was diluted with EtOAc (30 mL). Themixture was added H₂O (10 mL) and stirred for 1 min to give yellowsuspension. The suspension was filtered. The filtrate was washed withH₂O (20 mL×3), dried with anhydrous Na₂SO₄, filtered and concentrated invacuum to afford the title compound (3.77 g, 17.428 mmol, 98.59% yield)as yellow solid.

(R)-2-methyl-N-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-2-propanesulfinamide

To a mixture of(R)-2-methyl-N—[(E)-1,3-thiazol-5-ylmethylene]-2-propanesulfinamide(3.77 g, 17.43 mmol) in THF (37 mL) was added chloro(methyl)magnesium(9.88 mL, 29.63 mmol) at −40° C. The reaction mixture was stirred at 25°C. for 16 h to give black brown mixture. TLC (100% EtOAc) showed thestarting material was consumed completely, and one new spot (Rf=0.3) wasdetected. The reaction mixture was quenched with NH₄Cl (60 mL). Theresulting mixture was extracted with EtOAc (40 mL×4). The combinedorganic phase was washed with brine (80 mL×2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum to give a residue. Theresidue was purified by flash column (10% EtOAc in PE to 100% EtOAc) toafford the title compound (1.7 g, 7.3159 mmol, 41.978% yield) as brownoil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.77 (s, 1H), 7.84 (s, 1H), 5.00-4.60(m, 1H), 3.52 (d, J=3.2 Hz, 1H), 1.69 (d, J=6.4 Hz, 3H), 1.23 (s, 9H).(1 S)-1-(1,3-thiazol-5-yl)ethanamine

A solution of(R)-2-methyl-N-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-2-propanesulfinamide(500 mg, 2.15 mmol) in MeOH/HCl (8 mL, 2.15 mmol) was stirred at 25° C.for 2 h to give brown mixture. TLC (100% EtOAc) showed the startingmaterial was consumed completely. The reaction mixture was concentratedin vacuo to give a residue. The residue was triturated with MTBE (20 mL)and dried in vacuo to give the title compound (504 mg, 3.0609 mmol,142.25% yield) (crude) as brown solid.

ethyl 1-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-1H-imidazole-4-carboxylate

To a mixture of (1S)-1-(1,3-thiazol-5-yl)ethanamine (350 mg, 2.13 mmol)in 1-Butanol (3.5 mL) were added ethyl(2Z)-3-(dimethylamino)-2-isocyanoacrylate (357.5 mg, 2.13 mmol) and Et₃N(0.41 mL, 3.19 mmol). The reaction mixture was stirred at 130° C. for 1h used MW to give brown mixture. The reaction mixture was concentratedin vacuo to give a residue. The residue was purified by prep-TLC (100%EtOAc) to afford the title compound (46 mg, 0.1830 mmol, 8.6116% yield)as brown solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.83 (s, 1H), 7.81 (s, 1H), 7.66 (s,1H), 7.62 (s, 1H), 5.75-5.60 (m, 1H), 4.37 (q, J=7.6 Hz, 2H), 2.00 (d,J=7.2 Hz, 3H), 1.39 (t, J=7.6 Hz, 3H).1-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-1H-imidazole-4-carboxylic acid

To a mixture ethyl1-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-1H-imidazole-4-carboxylate (46 mg,0.1800 mmol) in THF (1.5 mL) and H₂O (0.50 mL) was added LiOH.H₂O (0.02mL, 0.2700 mmol). The reaction mixture was stirred at 25° C. for 16 h togive yellow mixture. The reaction mixture was diluted with H₂O (4 mL)and extracted with EtOAc (2 mL×3). The aqueous phase was acidified with1 N HCl aq. to pH=5 and lyophilized to afford the title compound (40 mg,0.1792 mmol, 97.882% yield) as brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ=9.06 (s, 1H), 7.93 (s, 1H), 7.90 (s, 1H),7.76 (s, 1H), 6.05-5.95 (m, 1H), 1.89 (d, J=6.8 Hz, 3H).

[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-1H-imidazol-4-yl}methanone

To a mixture of1-[(1S)-1-(1,3-thiazol-5-yl)ethyl]-1H-imidazole-4-carboxylic acid (40mg, 0.1800 mmol) in DMF (0.8286 mL) were added HATU (82.2 mg, 0.2200mmol) and DIPEA (0.15 mL, 0.9000 mmol). The mixture was stirred at 50°C. for 30 min and followed by addition of(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (48.44 mg, 0.2700 mmol). The mixture was stirred at 25° C.for 16 h to give a yellow mixture. The reaction mixture was purified byprep-HPLC (NH₃). The afforded flows were combined, concentrated toremove most of CH₃CN and lyophilized to afford the title compound (14.11mg, 0.0366 mmol, 20.34% yield) as yellow solid.

LC-MS Method1: 386.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.80 (s, 1H), 7.79 (s, 1H), 7.67(s, 1H), 7.52 (d, J=1.4 Hz, 1H), 5.68 (d, J=7.0 Hz, 1H), 4.71 (t, J=11.3Hz, 1H), 4.16 (dd, J=12.6, 1.9 Hz, 1H), 3.87-3.99 (m, 1H), 3.60 (dd,J=12.6, 4.2 Hz, 1H), 2.63 (s, 2H), 2.08 (dt, J=7.3, 3.7 Hz, 1H), 1.98(d, J=7.0 Hz, 4H), 1.45 (br d, J=4.0 Hz, 1H), 1.37 (s, 6H).

Example 29[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-1-phenylpropan-2-yl]-1H-imidazol-4-yl}methanone(2R)-1-phenyl-2-propanyl 4-methylbenzenesulfonate

To a solution of (2R)-1-phenyl-2-propanol (400 mg, 2.94 mmol) in DCM (5mL) were added Et₃N (0.45 mL, 3.23 mmol) and 4-methylbenzene-1-sulfonylchloride (0.44 mL, 2.94 mmol). The reaction was stirred at 20° C. for 16hr to give a yellow solution. TLC (PE/EA=10/1, rf=0.3) showed a newmajor spot. H₂O (30 mL) was added and it was extracted with DCM (30mL×2). The combined organic layer was dried over Na₂SO₄ and concentratedin vacuum to give a yellow oil. The crude was purified by silica gelchromatography (PE/EA=1/0 to 10/1) to give the title compound (680 mg,2.3418 mmol, 79.731% yield) as a white solid.

methyl 1-[(2S)-1-phenylpropan-2-yl]-1H-imidazole-4-carboxylate

A solution of methyl 1H-imidazole-4-carboxylate (300 mg, 2.38 mmol) and(2R)-1-phenyl-2-propanyl 4-methylbenzenesulfonate (690.78 mg, 2.38 mmol)in DMF (4 mL) was stirred at 80° C. for 16 hr to give a yellow solution.H₂O (30 mL) was added and it was extracted with EtOAc (30 mL×2). Thecombined organic layer dried over Na₂SO₄ and concentrated in vacuum togive a yellow oil. The crude was purified by silica gel chromatography(DCM/EA=10/1 to 3/1) to give the title compound (120 mg, 0.4912 mmol,20.649% yield)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (s, 1H), 7.35-7.15 (m, 5H),6.95-6.85 (m, 2H), 4.45-4.35 (m, 1H), 3.88 (s, 3H), 3.10-2.90 (m, 2H),1.56 (d, J=6.8 Hz, 3H).1-[(2S)-1-phenylpropan-2-yl]-1H-imidazole-4-carboxylic acid

To a stirred solution of methyl1-[(2S)-1-phenylpropan-2-yl]-1H-imidazole-4-carboxylate (120 mg, 0.4900mmol) in 1,4-Dioxane (3 mL) was added a solution of LiOH.H₂O (41.22 mg,0.9800 mmol) in H₂O (1 mL, 0.4900 mmol). The reaction mixture as stirredat 20° C. for 16 h to give a colorless oil. TLC (PE/EA=1/1, Rf=0) showeda new spot. The reaction mixture was evaporated in vacuum andlyophilized to give the title compound (110 mg, 0.4777 mmol, 97.252%yield) as white solid.

[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-1-phenylpropan-2-yl]-1H-imidazol-4-yl}methanone

To a stirred solution of1-[(2S)-1-phenylpropan-2-yl]-1H-imidazole-4-carboxylic acid (100 mg,0.4300 mmol) and HATU (199.24 mg, 0.5200 mmol) in DMF (3 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.37 mL, 2.17 mmol). After stirredfor 30 mins,(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (109.95 mg, 0.4300 mmol) was added and the reaction wasstirred at 20° C. for 16 hr to give a yellow solution. H₂O (30 mL) wasadded and it was extracted with EtOAc (30 mL×2). The combined organiclayer dried over Na₂SO₄ and concentrated in vacuum to give a yellow oil.The crude was purified by Prep-HPLC (NH₃). The afforded flows wereconcentrated in vacuum to remove most of CH₃CN and lyophilized to givethe title compound (104.7 mg, 0.2668 mmol, 61.424% yield) as whitesolid.

LC-MS Method1: 393.3 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.64 (s, 1H), 7.21-7.26 (m, 3H), 7.17(br s, 1H), 6.96 (br d, J=7.03 Hz, 2H), 4.69 (br d, J=12.05 Hz, 1H),4.30-4.38 (m, 1H), 4.18 (br d, J=10.54 Hz, 1H), 3.86-3.95 (m, 1H), 3.60(br dd, J=3.89, 12.42 Hz, 1H), 2.94-3.04 (m, 2H), 2.63 (s, 2H), 2.06 (brd, J=3.51 Hz, 1H), 1.97 (br d, J=3.51 Hz, 1H), 1.54 (d, J=6.78 Hz, 3H),1.46 (br d, J=11.29 Hz, 1H), 1.37 (s, 6H)

Example 30[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-4-phenylbutan-2-yl]-1H-imidazol-4-yl}methanone(R)-2-methyl-N-[(1E)-1-methyl-3-phenylpropanylidene]-2-propanesulfinamide

To a mixture of 4-phenyl-2-butanone (1.01 mL, 6.75 mmol) in THF (10 mL)were added (R)-2-methylpropane-2-sulfinamide (817.81 mg, 6.75 mmol) andTi(OEt)₄ (2307.69 mg, 10.12 mmol). The reaction mixture was stirred at60° C. for 16 h to give yellow mixture. The reaction mixture was dilutedwith EtOAc (30 mL). The mixture was added to H₂O (10 mL) and stirred for1 min to give yellow suspension. The suspension was filtered. Thefiltrate was washed with H₂O (20 mL×3), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum to give a residue. The residue waspurified by flash column (PE to 30% EtOAc in PE) to give the titlecompound (570 mg, 2.2674 mmol, 33.603% yield) as yellow oil.

LC-MS Method1 0.823 min, MS (m/z) 252 (M+H⁺).

(R)-2-methyl-N-[(2S)-4-phenylbutan-2-yl]-2-propanesulfinamide

To a mixture of(R)-2-methyl-N—[(E1)-1-methyl-3-phenylpropanylidene]-2-propanesulfinamide(570 mg, 2.27 mmol) in THF (6 mL) was added L-selectride (6.8 mL, 6.8mmol) at 0° C. The mixture was stirred at 25° C. for 3 h to givecolorless mixture. TLC (PE:EtOAc=2:1) showed one new spot (Rf=0.3) wasdetected. The reaction was quenched by H₂O (3 mL). The reaction mixturewas concentrated in vacuo to give a residue. The residue was purified byflash column (PE to 30% EtOAc in PE) to afford the title compound (260mg, 1.026 mmol, 45.252% yield) as yellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.40-7.25 (m, 2H), 7.25-7.10 (m,3H), 3.41 (qn, J=6.8 Hz, 1H), 2.93 (d, J=7.2 Hz, 1H), 2.80-2.55 (m, 2H),1.95-1.75 (m, 2H), 1.33 (d, J=6.8 Hz, 3H), 1.24 (s, 9H).(2S)-4-phenyl-2-butanamine

A solution of(R)-2-methyl-N-[(2S)-4-phenylbutan-2-yl]-2-propanesulfinamide (260 mg,1.03 mmol) in MeOH/HCl (5 mL, 1.03 mmol) was stirred at 25° C. for 1 hto give yellow mixture. The reaction mixture was concentrated in vacuoto afford the title compound (190 mg, 1.0232 mmol, 99.724% yield)(crude) as yellow solid.

ethyl 1-[(2S)-4-phenylbutan-2-yl]-1H-imidazole-4-carboxylate

To a mixture of (2S)-4-phenyl-2-butanamine (190 mg, 1.02 mmol) in1-Butanol (2 mL) were added ethyl(2Z)-3-(dimethylamino)-2-isocyanoacrylate (172.09 mg, 1.02 mmol) andEt₃N (0.2 mL, 1.53 mmol). The reaction mixture was heated in microwavesystem at 130° C. for 1 h to give brown mixture. TLC (PE:EtOAc=1:1)showed one new spot (Rf=0.2) was detected. The reaction mixture wasconcentrated in vacuo to give a residue. The residue was purified byprep-TLC (PE:EtOAc=1:1) to afford the title compound (40 mg, 0.1469mmol, 14.354% yield) as brown oil.

LC-MS Method1 0.718 min, MS (m/z) 273 (M+H⁺).

1-[(2S)-4-phenylbutan-2-yl]-1H-imidazole-4-carboxylic acid

To a mixture of ethyl1-[(2S)-4-phenylbutan-2-yl]-1H-imidazole-4-carboxylate (40 mg, 0.1500mmol) in THF (1.5 mL) and H₂O (0.50 mL) was added LiOH.H₂O (0.01 mL,0.2200 mmol). The reaction mixture was stirred at 40° C. for 16 h togive yellow mixture. TLC (PE:EtOAc=1:1) showed the starting material wasconsumed completely. The reaction mixture was diluted with H₂O (5 mL)and extracted with EtOAc (3 mL×2). The aqueous phase was acidified with1 N HCl aq. to pH=5 and lyophilized to afford the title compound (30 mg,0.1228 mmol, 83.612% yield) as yellow solid.

LC-MS Method1 0.677 min, MS (m/z) 245 (M+H⁺).

[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-4-phenylbutan-2-yl]-1H-imidazol-4-yl}methanone

To a mixture of 1-[(2S)-4-phenylbutane-2-yl]1H-imidazole-4-carboxylicacid (30 mg, 0.1200 mmol) in Pyridine (1.5 mL) was added EDCI (28.25 mg,0.1500 mmol). The mixture was stirred at 25° C. for 10 min and followedby addition of(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (26.61 mg, 0.1200 mmol). The mixture was stirred at 25° C.for 16 h to give a yellow mixture. LCMS showed the starting material wasconsumed completely. The reaction mixture was concentrated in vacuo togive a residue. The residue was purified by prep-HPLC (NH₃). Theafforded flows were combined, concentrated to remove most of CH₃CN andlyophilized to afford the title compound (16.26 mg, 0.0449 mmol, 17.643%yield) as yellow solid.

LC-MS Method1: 407.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.68 (s, 1H), 7.43 (s, 1H),7.28-7.32 (m, 2H), 7.19-7.24 (m, 1H), 7.12 (s, 1H), 7.10 (s, 1H), 4.78(dd, J=11.8, 3.8 Hz, 1H), 4.21 (br d, J=12.5 Hz, 1H), 4.04-4.15 (m, 1H),3.97 (br d, J=11.5 Hz, 1H), 3.63 (dd, J=12.4, 3.9 Hz, 1H), 2.65 (s, 2H),2.39-2.60 (m, 2H), 2.05-2.19 (m, 3H), 1.99 (br d, J=3.5 Hz, 1H), 1.50(d, J=6.8 Hz, 3H), 1.46-1.49 (m, 1H), 1.38 (s, 6H)

Example 31[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-1-phenoxypropan-2-yl]-1H-imidazol-4-yl}methanonetert-butyl [(2S)-1-phenoxypropan-2-yl]carbamate

To a solution of phenol (0.51 mL, 5.84 mmol), tert-butyl[(2S)-1-hydroxypropan-2-yl]carbamate (1024.08 mg, 5.84 mmol), PPh₃(2299.32 mg, 8.77 mmol) in Toluene (12 mL) was slowly added DIAD (1.73mL, 8.77 mmol). The reaction mixture was stirred at 20° C. for 16 hr togive a yellow solution. TLC (PE/EA=10/1, Rf=0.8) showed a new spot. H₂O(30 mL) was added and it was extracted with EtOAc (30 mL×2). Thecombined organic layer dried over Na₂SO₄ and concentrated in vacuum togive a yellow oil. The crude was purified by silica gel chromatography(PE/EA=10/1 to 3/1) to give the title compound (600 mg, 2.3874 mmol,40.85% yield) as white solid.

(2S)-1-phenoxy-2-propanamine hydrochloride

To a solution of tert-butyl [(2S)-1-phenoxypropan-2-yl]carbamate (1100mg, 4.38 mmol) in MeOH (1 mL) was added HCl/dioxane (5 mL, 20 mmol) andthe reaction mixture was stirred at 20° C. for 3 hr to give a colorlesssolution. LCMS showed a new peak gives the desired ms. The reactionmixture was evaporated in vacuum to give the title compound (800 mg,4.2628 mmol, 97.393% yield) as yellow solid. It was used directly in thenext step.

LC-MS Method1 0.498 min, MS (m/z) 151.8 (M+H⁺).

ethyl 1-[(2S)-1-phenoxypropan-2-yl]-1H-imidazole-4-carboxylate

To a 5 mL MW vial were added (2S)-1-phenoxy-2-propanamine hydrochloride(1100 mg, 5.86 mmol), ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate(985.82 mg, 5.86 mmol), 1-Butanol (3 mL) and Et₃N (1.22 mL, 8.79 mmol).The reaction was irradiated with microwave at 130° C. for 1 hr to give abrown solution. LCMS showed a new peak gives the desired ms. Thereaction was diluted with sat. Na₂CO₃ aq. (20 mL). H₂O (30 mL) was addedand it was extracted with EtOAc (30 mL×2). The combined organic layerdried over Na₂SO₄ and concentrated in vacuum to give a yellow oil. Thecrude was purified by silica gel chromatography (PE/EA=10/1 to 1/1) togive the title compound (310 mg, 1.1301 mmol, 19.28% yield) as whitesolid.

LC-MS Method1 0.765 min, MS (m/z) 275.2 (M+H⁺).

1-[(2S)-1-phenoxypropan-2-yl]-1H-imidazole-4-carboxylic acid

A stirred solution of ethyl1-[(2S)-1-phenoxypropan-2-yl]-1H-imidazole-4-carboxylate (310 mg, 1.13mmol) in 1,4-Dioxane (3 mL) was added a solution of LiOH.H₂O (61.64 mg,1.47 mmol) in H₂O (ml, 1.13 mmol). The reaction mixture was stirred at20° C. for 16 hr to give a yellow solution. LCMS showed a new peak givethe desired ms. H₂O (30 mL) was added and it was extracted with EtOAc(30 mL). Then aqueous layer was acidified by 1M HCl aq. and lyophilizedto give the title compound (240 mg, 0.9746 mmol, 86.241% yield) as ayellow solid.

LC-MS Method1 0.645 min, MS (m/z) 247.2 (M+H⁺).

[(1R,5S,6S)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]{1-[(2S)-1-phenoxypropan-2-yl]-1H-imidazol-4-yl}methanone

A stirred solution of1-[(2S)-1-phenoxypropan-2-yl]-1H-imidazole-4-carboxylic acid (130 mg,0.5300 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.45 mL, 2.64 mmol)in DMF (2 mL) was added HATU (300.9 mg, 0.7900 mmol). After stirred for30 mins,(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (114.4 mg, 0.5300 mmol) was added to give a brownsolution. H₂O (30 mL) was added and it was extracted with EtOAc (30mL×2). The combined organic layer dried over Na₂SO₄ and concentrated invacuum to give a yellow oil. The crude was purified by prep-HPLC (NH₃).The afforded flows were concentrated in vacuum to remove most of CH₃CNand lyophilized to give the title compound (51.22 mg, 0.1254 mmol,23.752% yield) as white solid.

LC-MS Method1: 409.3 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (s, 6H) 1.47 (br s, 1H) 1.64(d, J=7.03 Hz, 3H) 2.00-2.15 (m, 2H) 2.72 (s, 2H) 3.53-3.67 (m, 1H) 3.92(br d, J=8.53 Hz, 1H) 4.10 (br d, J=12.30 Hz, 1H) 4.15-4.28 (m, 2H) 4.37(br d, J=10.79 Hz, 1H) 4.75 (br dd, J=11.04, 6.78 Hz, 1H) 6.88 (br d,J=8.03 Hz, 2H) 6.92 (br t, J=7.53 Hz, 1H) 7.24 (br t, J=7.65 Hz, 2H)7.82 (br d, J=6.78 Hz, 2H)

Example 32[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(pentan-3-yl)-1H-imidazol-4-yl]methanoneethyl 1-(pentan-3-yl)-1H-imidazole-4-carboxylate

The mixture of pentan-3-amine (1.73 mL, 14.86 mmol) and ethyl(2Z)-3-(dimethylamino)-2-isocyanoacrylate (500 mg, 2.97 mmol) wasstirred at 80° C. for 16 hours. The crude product was purified by flashcolumn (PE:EA=2:1) to give the title compound (500 mg, 2.3779 mmol,79.988% yield) as a brown oil.

1-(pentan-3-yl)-1H-imidazole-4-carboxylic acid

To a solution of ethyl 1-(pentan-3-yl)-1H-imidazole-4-carboxylate in THF(15 mL) and H₂O (5 mL) was added LiOH.H₂O (0.41 mL, 7.13 mmol). Thereaction mixture was stirred at 40° C. for 16 hours to give a yellowmixture. The reaction mixture was concentrated in vacuum to remove mostof THF. The residue was diluted with H₂O (5 mL) and acidified with 0.5 MHCl aq. to pH=6. Then the solution was lyophilized to give the titlecompound as a yellow solid.

[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(pentan-3-yl)-1H-imidazol-4-yl]methanone

To a solution of 1-(pentan-3-yl)-1H-imidazole-4-carboxylic acid (50 mg,0.2700 mmol) in DMF (5 mL) were added HATU (157.35 mg, 0.4100 mmol) andEt₃N (0.14 mL, 1.1 mmol) and the reaction mixture was stirred for 15 minat 25° C. Then(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (49.46 mg, 0.2700 mmol) was added. The resulting mixturewas stirred for 2 hours at 25° C. to give a brown solution, and thenconcentrated in vacuum to remove most of DMF to give a crude product.The crude product was purified by Prep-HPLC (NH₃) to give the titlecompound as a white solid.

LC-MS Method1: 345.3 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.61 (d, J=1.3 Hz, 1H), 7.40 (d, J=1.3Hz, 1H), 4.80 (d, J=12.0 Hz, 1H), 4.20 (d, J=12.5 Hz, 1H), 3.95 (dd,J=4.0, 11.8 Hz, 1H), 3.74 (tt, J=4.8, 9.5 Hz, 1H), 3.62 (dd, J=4.3, 12.3Hz, 1H), 2.65 (s, 2H), 2.13-2.05 (m, 1H), 2.02-1.95 (m, 1H), 1.91-1.79(m, 2H), 1.78-1.69 (m, 2H), 1.48 (t, J=3.4 Hz, 1H), 1.38 (s, 6H), 0.82(t, J=7.3 Hz, 6H)

Example 33[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone

ethyl 1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylate

To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (469.02mg, 2.79 mmol) in 1-Butanol (5.5 mL) were added 1-methylcyclopropanamine(300 mg, 2.79 mmol) and Et₃N (0.54 mL, 4.18 mmol). The resulting mixturewas subjected to reaction in microwave reactor (time: 1 h, temp: 130°C.). TLC (PE:EtOAc=0:1) showed the reaction was completed (Rf=0.5). Thereaction mixture was concentrated directly. The crude product waspurified by flash column (PE to 40% EtOAc in PE) to afford the titlecompound (118 mg, 0.6075 mmol, 21.786% yield) as a brown oil.

LC-MS Method1: 0.568 min, MS (m/z) 194.9 [M+H]⁺

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.71-7.69 (m, 1H), 7.60 (s, 1H), 4.36(q, J=7.0 Hz, 2H), 1.58 (s, 3H), 1.38 (t, J=7.2 Hz, 3H), 1.17-1.12 (m,2H), 0.96-0.91 (m, 2H) 1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylicacid

To a solution of ethyl1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylate (118 mg, 0.61 mmol)in THF (1.5 mL) and H₂O (0.50 mL) was added LiOH.H₂O (0.05 mL, 0.79mmol). The resulting mixture was stirred at 20-25° C. for 2 h. Thereaction mixture was concentrated directly. The residue was acidifiedwith 1 M HCl aq. to pH=6 and then lyophilized to afford the titlecompound (100 mg, 0.6018 mmol, 99.05% yield) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=7.81 (d, J=1.0 Hz, 1H), 7.65 (s, 1H),1.55-1.47 (m, 3H), 1.13-1.07 (m, 2H), 0.91-0.85 (m, 2H)

[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone

To a solution of 1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylic acid(100 mg, 0.60 mmol) in DMF (2 mL) were added HATU (276.06 mg, 0.72 mmol)and Et₃N (0.39 ML, 3.01 mmol). The mixture was stirred at 20-25° C. for0.5 h. The mixture was added(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (108.47 mg, 0.60 mmol). The reaction mixture was stirredat 20-25° C. for 1 h. LCMS showed the desired MS (as a major peak). Theresidue was purified by prep-HPLC (NH₃). The afforded flows werecombined, concentrated to remove most of CH₃CN and lyophilized to affordthe title compound (60.45 mg, 0.1841 mmol, 30.589% yield) as a yellowsolid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (d, J=1.5 Hz, 1H), 7.52 (d, J=1.3Hz, 1H), 4.70 (d, J=11.8 Hz, 1H), 4.18 (d, J=12.5 Hz, 1H), 3.92 (dd,J=4.0, 12.0 Hz, 1H), 3.60 (dd, J=4.1, 12.4 Hz, 1H), 2.63 (s, 2H), 2.07(br dd, J=3.5, 7.0 Hz, 1H), 2.01-1.92 (m, 1H), 1.57 (s, 3H), 1.45 (t,J=3.4 Hz, 1H), 1.37 (s, 6H), 1.16-1.10 (m, 2H), 0.95-0.89 (m, 2H)LC-MS Method1 0.606 min, MS (m/z) 329.0 [M+H⁺]

Example 34[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclobutyl)-1H-imidazol-4-yl]methanoneethyl 1-(1-methylcyclobutyl)-1H-imidazole-4-carboxylate

To a mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (200 mg,1.19 mmol) in 1-Butanol (0.50 mL) were added 1-methylcyclobutanamine(583.25 mg, 4.76 mmol) and Et₃N (1.15 mL, 8.92 mmol). The resultingmixture was heated at 76° C. for 16 hr. The reaction mixture was dilutedwith H₂O (5 mL) and extracted with EtOAc (5 mL×3). The combined organiclayers were separated, washed with brine (10 mL), dried over Na₂SO₄ andconcentrated in vacuum to give crude oil. The crude oil was purified byprep-TLC (100% EA) to give the title compound (50 mg, 0.2401 mmol,20.19% yield) as yellow oil.

LC-MS Method1 0.665 min, MS (m/z) 209.2 (M+H⁺).

1-(1-methylcyclobutyl)-1H-imidazole-4-carboxylic acid

To a mixture of ethyl 1-(1-methylcyclobutyl)-1H-imidazole-4-carboxylate(50 mg, 0.2400 mmol) in H₂O (0.4952 mL) and MeOH (0.3961 mL) was addedLiOH.H₂O (0.04 mL, 0.7200 mmol). The resulting mixture was stirred at25° C. for 5 hr. The aqueous phase was washed with DCM (3 mL×2) andacidified with 1N HCl to pH=2. The aqueous solution was lyophilized togive the title compound (50 mg, 0.2775 mmol, 115.57% yield) as paleyellow solid.

[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclobutyl)-1H-imidazol-4-yl]methanone

To a mixture of 1-(1-methylcyclobutyl)-1H-imidazole-4-carboxylic acid(48.08 mg, 0.2200 mmol) in DMF (0.40 mL) were added HATU (137.86 mg,0.3600 mmol), DIPEA (0.18 mL, 1.11 mmol) and(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (40 mg, 0.2200 mmol). The resulting mixture was stirred at20° C. for 4 hr. The reaction mixture was diluted with H₂O (5 mL) andextracted with EtOAc (5 mL×2), then washed with brine (8 mL). Thecombined organic layers were separated, then dried over Na₂SO₄ andconcentrated in vacuum to give crude oil. The crude oil was purified byprep-HPLC (NH₃) and then lyophilized to give the title compound (3 mg,0.0088 mmol, 3.9478% yield) as pale yellow solid.

¹H NMR (400 MHz, CD₃OD) 5=7.74 (s, 1H), 7.67 (s, 1H), 4.41 (br d, J=12.0Hz, 1H), 4.09 (br d, J=12.3 Hz, 1H), 3.93 (br dd, J=3.8, 11.8 Hz, 1H),3.59 (br dd, J=3.9, 12.4 Hz, 1H), 2.71 (s, 2H), 2.63-2.52 (m, 2H), 2.30(tt, J=3.0, 8.9 Hz, 2H), 2.14-2.08 (m, 1H), 2.07-1.92 (m, 3H), 1.68 (s,3H), 1.48 (t, J=3.4 Hz, 1H), 1.32 (s, 6H).

Example 35[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-propyl-1H-imidazol-4-yl)methanoneethyl 1-propyl-1H-imidazole-4-carboxylate

To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (500mg, 2.97 mmol) in 1-Butanol (0.5 M, 64.98 mmol) were addedpropan-1-amine (2.97 mL, 1.78 mmol, 1.0 eq.) and Et₃N (0.25 mL, 1.78mmol, 0.6 eq.). The mixture was stirred at 130° C. for 6 hr, and thenconcentrated to give a residue. The residue was purified by silica gelchromatography (n-haxane/EtOAc=60/40 to 0/100 and then MeOH/EtOAc=5/95)to give the title compound (214 mg, 1.17 mmol, 39.5% yield) as a brownoil.

LC-MS Method1 0.662 min, MS (m/z) 183.0 (M+H⁺).

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.60 (d, J=1.2 Hz, 1H), 7.47 (d, J=1.2Hz, 1H), 4.36 (q, J=7.2 Hz, 2H), 3.93 (t, J=6.9 Hz, 2H), 1.90-1.80 (m,2H), 1.39 (t, J=6.9 Hz, 3H), 0.94 (t, J=9.6 Hz, 3H).1-propyl-1H-imidazole-4-carboxylic acid

To a stirred solution of ethyl 1-propyl-1H-imidazole-4-carboxylate (214mg, 1.17 mmol) in THF (1.7 mL, 660 mM) was added a solution of LiOH(70.3 mg, 2.94 mmol, 2.5 eq.) in H₂O (0.6 mL). The reaction mixture wasstirred at 40° C. for 12 hr. The reaction mixture was diluted with H₂Oand extracted with DCM. The aqueous phase was acidified with 1 N HCl(aq) to pH=5. The resulting aqueous phase was dried in vacuum to affordthe title compound (133 mg, 0.86 mmol, 73.4% yield) (crude) as beigesolid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.81 (d, J=1.5 Hz, 1H), 7.72 (d, J=1.5 Hz,1H), 3.94 (t, J=6.9 Hz, 2H), 1.80-1.60 (m, 2H), 0.78 (t, J=7.5 Hz, 3H).

[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-propyl-1H-imidazol-4-yl)methanone

To a stirred solution of 1-propyl-1H-imidazole-4-carboxylic acid (45.0mg, 0.14 mmol) and HATU (53.2 mg, 0.14 mmol, 1.0 eq.) in THF (0.7 mL,200 mM) was added DIPEA (0.12 mL, 0.7 mmol, 5.0 eq.). After stirred at50° C. for 30 min,(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (33.4 mg, 0.154 mmol, 1.1 eq.) was added and the reactionwas stirred at 20° C. for 16 hr to give a yellow solution. H₂O was addedand it was extracted with DCM. The combined organic layer dried overNa₂SO₄ and concentrated in vacuum to give a yellow oil. The crude waspurified by silica gel chromatography (EtOAc/DCM=99/1 to 70/30) to givethe title compound (23 mg, 0.072 mmol, 51.9% yield) as a beige powder.

LC-MS Method1 0.757 min, MS (m/z) 317.0 (M+H⁺).¹H NMR (400 MHz, CHLOROFORM-d) δ 7.59 (d, J=1.5 Hz, tH), 7.39 (d, J=1.5Hz, 1H), 4.73 (d, J=11.2 Hz, 1H), 4.18 (d, J=11.2 Hz, 1H), 4.00-3.85 (m,1H), 3.91 (t, J=7.2 Hz, 2H), 3.65-3.55 (m, 1H), 2.64 (s, 2H), 2.10-2.05(m, 1H), 2.05-1.90 (m, 1H), 1.90-1.70 (m, 2H), 1.50-1.45 (m, 1H), 1.37(s, 6H), 0.91 (t, 3H, J=7.2 Hz, 3H).

Example 36[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isobutyl-1H-imidazol-4-yl)methanoneethyl 1-isobutyl-1H-imidazole-4-carboxylate

To a solution of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (1.50g, 8.92 mmol) in 1-Butanol (17.8 mL, 0.5 M) were added2-methylpropan-1-amine (1.0 mL, 9.8 mmol, 1.1 eq.) and Et₃N (0.74 mL,5.35 mmol, 0.6 eq.). The mixture was stirred at 130° C. for 6 h and thenconcentrated to give a residue. The residue was purified by silica gelchromatography (n-haxane/EtOAc=60/40 to 0/100 and then MeOH/EtOAc=5/95)to give the title compound (455 mg, 2.3 mmol, 26.0% yield) as a brownoil.

LC-MS Method1 0.743 min, MS (m/z) 197.0 (M+H⁺).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=1.2 Hz, 1H), 7.44 (d,J=1.2 Hz, 1H), 4.36 (q, J=7.2 Hz, 2H), 3.75 (d, J=7.8 Hz, 2H), 2.15-1.95(m, 1H), 1.39 (t, J=7.2 Hz, 3H), 0.93 (d, J=6.6 Hz, 6H).1-isobutyl-1H-imidazole-4-carboxylicacid

A stirred solution of ethyl 1-isobutyl-1H-imidazole-4-carboxylate (450mg, 2.3 mmol) in THF (3.5 mL, 660 mM) was added a solution of LiOH (137mg, 5.7 mmol, 2.5 eq.) in H₂O (1.2 mL). The reaction mixture was stirredat 40° C. for 12 hr, and then diluted with H₂O and extracted with DCM.The aqueous phase was acidified with 1 N HCl (aq) to pH=5. The resultingaqueous phase was dried in vacuum to afford the title compound (440 mg,2.15 mmol, 93.8% yield) (crude) as yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.50 brs, 1H), 8.10 (d, J=1.2 Hz, 1H),3.91 (d, J=6.9 Hz, 2H), 2.15-1.95 (m, 1H), 0.82 (d, J=6.6 Hz, 6H).

[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isobutyl-1H-imidazol-4-yl)methanone

To a stirred solution of 1-isobutyl-1H-imidazole-4-carboxylicacid (65.0mg, 0.15 mmol) and HATU (56.8 mg, 0.15 mmol, 1.0 eq.) in THF (0.7 mL,200 mM) was added DIPEA (0.13 mL, 0.75 mmol, 5.0 eq.). After stirred at50° C. for 30 min,(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (35.6 mg, 0.164 mmol, 1.1 eq.) was added and the reactionwas stirred at 50° C. for 1 hr to give a yellow solution. H₂O was addedand it was extracted with DCM. The combined organic layer dried overNa₂SO₄ and concentrated in vacuum to give a yellow oil. The crude waspurified by silica gel chromatography (EtOAc/DCM=99/1 to 80/20) to givethe title compound (36.2 mg, 0.11 mmol, 73.4% yield) as a white powder.

LC-MS Method1 0.800 min, MS (m/z) 331.1 (M+H⁺).¹H NMR (300 MHz, CHLOROFORM-d) δ 7.57 (d, J=1.8 Hz, 1H), 7.36 (d, J=1.8Hz, 1H), 4.74 (d, J=12.3 Hz, 1H), 4.18 (d, J=12.3 Hz, 1H), 3.93 (dd,J=12.3, 4.2 Hz, 1H), 3.73 (d, J=7.2 Hz, 2H), 3.61 (dd, J=12.3, 4.2 Hz,1H), 2.64 (s, 2H), 2.15-1.95 (m, 3H), 1.50-1.40 (m, 1H), 1.37 (s, 6H),0.92 (d, J=6.6 Hz, 6H).

Example 37(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

tert-butyl(1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

The mixture of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 0.77 mmol) in DMF (2 mL) were added prop-1-ene (4.6 mL, 2.3mmol) and Et₃N (0.38 mL, 2.3 mmol). The resulting mixture was stirred at20° C. for 16 hr to give pale yellow mixture. The reaction mixture wasdiluted with H₂O (10 mL), then extracted with EtOAc (10 mL×2). Thecombined organic layers were separated, then dried over Na₂SO₄ andconcentrated in vacuum to give the title compound (130 mg, crude) aspale yellow oil.

LC-MS Method1 0.825 min, MS (m/z) 267.0 (M+H⁺).

(1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride

To tert-butyl(1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(130 mg, 0.49 mmol) was added HCl/dioxane (3. mL, 0.49 mmol). Thereaction mixture was stirred at 0° C. for 30 min to give pale yellowmixture. The reaction mixture was concentrated to dryness directly togive the title compound (90 mg, crude).

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of(1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (50 mg, 0.30 mmol) in DMF (0.50 mL) were added DIPEA (0.2mL, 1.2 mmol), 1-isopropylimidazole-4-carboxylic acid (46.38 mg, 0.30mmol) and HATU (148.6 mg, 0.39 mmol). The resulting mixture was stirredat 20° C. for 16 hr to give brown mixture. TLC (PE/EtOAc=0/1) showed aseries of new spots and 1-isopropylimidazole-4-carboxylic acid (46.38mg, 0.30 mmol) was consumed completely. LCMS detected desired MS. Thereaction mixture was diluted with H₂O (5 mL) and extracted with EtOAc (5mL×2), then washed with H₂O (5 mL) and brine (5 mL×2). The combinedorganic layers were separated, then dried over Na₂SO₄ and concentratedin vacuum to give crude product. The crude product was purified byprep-HPLC (NH₃) to give the title compound (5 mg, 0.0165 mmol, 5.4972%yield) as white solid.

1H NMR (400 MHz, MeOH) δ=7.69 (br d, J=14.6 Hz, 2H), 4.76-4.73 (m, 1H),4.74-4.73 (m, 1H), 4.42 (td, J=6.6, 13.4 Hz, 1H), 4.26 (br d, J=11.4 Hz,1H), 4.08-3.98 (m, 1H), 3.86 (br dd, J=3.6, 11.6 Hz, 1H), 3.54 (br d,J=9.9 Hz, 1H), 3.02-2.89 (m, 1H), 2.44 (dd, J=8.1, 16.9 Hz, 1H),2.13-1.95 (m, 2H), 1.42 (d, J=6.6 Hz, 6H), 1.18 (d, J=6.3 Hz, 3H)

Example 38(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonetert-butyl(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(0.24 mL, 24.32 mmol) were added methylenecyclopropane (300 mg, 1.22mmol) in THF (15 mL) and Et₃N (0.51 mL, 3.65 mmol). The reaction mixturewas stirred at 0° C. for 16 hr to give a yellow solution. LCMS showed anew peak gives the desired MS. The reaction mixture was diluted with H₂O(30 mL) and extracted with EtOAc (30 mL×2). The combined organic layerdried over Na₂SO₄ and concentrated to give the title compound (260 mg,0.9341 mmol, 76.809% yield) as yellow oil.

LC-MS Method1 0.845 min, MS (m/z) 279 (M+H⁺).

6-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-eneTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(260 mg, 0.93 mmol) in DCM (16.25 mL) was added 2,2,2-trifluoroaceticacid (0.07 mL, 0.93 mmol). The reaction mixture was stirred at 10° C.for 3 hr to give a yellow solution. LCMS showed a new peak give thedesired MS. The reaction mixture was evaporated in vacuum to give thetitle compound (272 mg, 0.9307 mmol, 99.64% yield) as yellow oil. Theproduct was used directly in the next step.

LC-MS Method1 0.178 min, MS (m/z) 179.1 (M+H⁺).

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

A 100 ml round-bottom flask was charged with1-isopropylimidazole-4-carboxylic acid (143.49 mg, 0.93 mmol), HATU(426.97 mg, 1.12 mmol), DMF (4.5916 mL) andN-ethyl-N-isopropylpropan-2-amine (0.48 mL, 2.79 mmol). After stirredfor 30 min,6-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-eneTFA salt (272 mg, 0.93 mmol) was added. The reaction mixture was stirredat 10° C. for 16 hr to give a yellow solution. LCMS showed the reactantwas completely consumed and the desired MS. The reaction mixture wasdiluted with H₂O (20 mL) and extracted with EtOAc (30 mL×2). Thecombined organic layer dried over Na₂SO₄ and concentrated to give yellowoil. The crude was purified by prep-HPLC (FA). The afford flows wereconcentrated in vacuum to remove most of CH₃CN and lyophilized to givethe title compound (14.67 mg, 0.0467 mmol, 5.0137% yield) as whitesolid.

LC-MS Method1: 315.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.67 (s, 1H), 7.48 (s, 1H), 4.73 (br d,J=12.0 Hz, 1H), 4.41-4.27 (m, 1H), 4.20 (br d, J=12.4 Hz, 1H), 3.95 (brdd, J=4.0, 12.0 Hz, 1H), 3.62 (br dd, J=4.0, 12.0 Hz, 1H), 2.96 (s, 2H),2.80 (s, 1H), 2.12 (br d, J=3.0 Hz, 1H), 2.03 (br d, J=3.5 Hz, 1H), 1.50(d, J=6.4 Hz, 6H), 1.14-1.08 (m, 2H), 0.73-0.67 (m, 2H)

Example 39(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonetert-butyl(1R,5S,6r)-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of tert-butyl(1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylatein DMF (1.5 mL) was added methylenecyclobutane (78.4 mg, 1.15 mmol). Thesuspension was stirred at 20° C. for 16 hr. The reaction mixture wasquenched with H₂O (10 mL). The residue was diluted with EtOAc (20 mL×3),washed with saturated NaCl (5 mL), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuum to afford the title compound (46 mg, crude)as yellow powder.

LC-MS Method1: 0.818 min, MS (m/z): 237.0 (M−56+H⁺).

7-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-5-oxa-6-azaspiro[3.4]oct-6-eneTFA salt

A mixture of tert-butyl(1R,5S,6r)-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(46.0 mg, 0.16 mmol) in DCM (1.5 mL) was added 2,2,2-trifluoroaceticacid (17.9 mg, 0.16 mmol). The suspension was stirred at 20° C. for 2hr. The reaction mixture was concentrated under reduced pressure to givethe title compound.

LC-MS Method1: 0.822 min, MS (m/z): 193.0 (M+H⁺).

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of7-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-5-oxa-6-azaspiro[3.4]oct-6-eneTFA salt (30.0 mg, 0.16 mmol) in Pyridine (0.5 mL) were added EDCI (29.9mg, 0.16 mmol) and 1-isopropylimidazole-4-carboxylic acid (24.1 mg, 0.16mmol). The suspension was stirred at 20° C. for 16 hr. The reactionmixture was quenched with H₂O (10 mL). The residue was diluted withEtOAc (20 mL×3), washed with saturated NaCl (5 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The solution was purifiedby prep-HPLC (NH₃) and lyophilized to afford the title compound (6.49mg, 12.7% yield) as yellow solid.

LC-MS Method1: 2.386 min, MS (m/z): 329.2 (M+H⁺).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.69 (d, J=1.51 Hz, 1H), 7.49 (d,J=1.51 Hz, 1H), 4.75 (d, J=12.05 Hz, 1H), 4.37 (dt, J=13.43, 6.84 Hz,1H), 4.20 (d, J=12.80 Hz, 1H), 3.93-3.99 (m, 1H), 3.63 (dd, J=12.92,3.89 Hz, 1H), 2.96 (s, 2H), 2.48 (dt, J=12.55, 9.66 Hz, 2H), 2.07-2.18(m, 4H), 2.02 (br d, J=9.03 Hz, 1H), 1.76-1.85 (m, 1H), 1.52 (d, J=6.78Hz, 7H), 1.49 (t, J=3.51 Hz, 1H).

Example 40{(1R,5S,6r)-6-[5-(difluoromethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanonetert-butyl(1R,5S,6r)-6-[5-(dihydroxymethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 0.77 mmol) and methacrylaldehyde (0.32 mL, 3.84 mmol) in DMF (3mL) was added Et₃N (0.22 mL, 1.53 mmol). The reaction was stirred at 20°C. for 12 h to give pale yellow solution. The reaction was diluted withEtOAc (15 mL), stirred with saturated NaHCO₃ (10 mL) for 5 min. Theaqueous layer was extracted with EtOAc (10 mL×2). The combined DCM layerwas dried over Na₂SO₄ and concentrated in vacuum to give the titlecompound (240 mg, 0.7683 mmol, crude) as pale brown oil.

tert-butyl(1R,5S,6r)-6-[5-(difluoromethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[5-(dihydroxymethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(240 mg, 0.77 mmol) in DCM (10 mL) was added DAST (371.11 mg, 2.31 mmol)at −78° C. The reaction was allowed to warm to 20° C. and stirred forfurther 12 h to give pale brown solution. The reaction was re-cooled to−78° C., treated with additional DAST (300 mg) and then allowed to warmto 20° C. and stirred for further 12 h to give pale brown solution. Thereaction was cooled to 0° C., diluted with DCM (20 mL), and quenchedwith saturated NaHCO₃ (8 mL). The organic layer was collected, driedover Na₂SO₄, and concentrated in vacuum to give crude oil, which waspurified by prep-HPLC (HCl). The afforded eluent was treated withsaturated NaHCO₃ (2 mL) and concentrated to remove MeCN. The residue wasextracted with EtOAC (10 mL×2). The combined EtOAc layer was dried overNa₂SO₄ and concentrated in vacuum to give the title compound (55 mg,0.1739 mmol, 22.628% yield) as pale brown gum.

¹H NMR (400 MHz, CHLOROFORM-d) δ=5.58 (t, J=56 Hz, 1H), 3.65 (d, J=11.2Hz, 1H), 3.56 (d, J=11.2 Hz, 1H), 3.36-3.32 (m, 2H), 3.04 (dd, J=17.2,6.0 Hz, 1H), 2.60 (d, J=17.2 Hz, 1H), 2.00-1.85 (m, 3H), 1.37 (s, 9H).1.37 (s, 3H).{(1R,5S,6r)-6-[5-(difluoromethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanone

To a solution of tert-butyl(1R,5S,6r)-6-[5-(difluoromethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(55 mg, 0.17 mmol) in DCM (2 mL) was added MeSO₃H (33.38 mg, 0.35 mmol).The reaction was stirred at 20° C. for 1 h to give pale yellow solution.DMF (1 mL) was added, followed by 1-isopropylimidazole-4-carboxylic acid(32.17 mg, 0.21 mmol), HATU (66.47 mg, 0.17 mmol) and Et₃N (0.12 mL,0.87 mmol). The resultant mixture was stirred at 20° C. for 12 h to giveyellow mixture. The reaction was concentrated and purified by prep-HPLC(NH₃). The afforded eluent was concentrated and lyophilized to give thetitle compound (7.01 mg, 0.0199 mmol, 11.442% yield) as a pale yellowsolid.

LC-MS Method1: 353.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.60 (d, J=1.4 Hz, 1H), 7.40 (d, J=1.4Hz, 1H), 5.78-5.37 (m, 1H), 4.70 (d, J=12.1 Hz, 1H), 4.28 (quin, J=6.7Hz, 1H), 4.13 (d, J=12.4 Hz, 11), 3.87 (br d, J=10.0 Hz, 1H), 3.54 (dd,J=3.9, 12.4 Hz, 1H), 3.05 (d, J=17.4 Hz, 1H), 2.61 (br dd, J=7.8, 17.6Hz, 1H), 2.04 (br s, 1U), 1.99-1.89 (m, 1H), 1.43 (d, J=6.6 Hz, 6H),1.38 (m, 3H)

Example 41[(1R,5S,6r)-6-(5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanonetert-butyl(1R,5S,6r)-6-(5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylatein DMF (1.5 mL) were added 2-methylbut-1-ene (403.48 mg, 5.75 mmol),Et₃N (116.4 mg, 1.15 mmol, 0.16 mL). The suspension was stirred at 20°C. for 16 hr. The reaction mixture was quenched with H₂O (10 mL). Theresidue was extracted with EtOAc (20 mL×3). The combined organic layerswere washed with saturated NaCl (5 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum. The residue was purified byprep-TLC (PE:EtOAc=2:1, Rf=0.5) to afford the title compound (76 mg,crude) as yellow powder.

LC-MS Method1: 0.833 min, MS (m/z): 239.0 (M−56+H⁺).

(1R,5S,6r)-6-(5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt

A mixture of compound tert-butyl(1R,5S,6r)-6-(5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(76.0 mg, 0.26 mmol), 2,2,2-trifluoroacetic acid (29.4 mg, 0.16 mmol) inDCM (1 mL) was stirred at 20° C. for 2 hr. The reaction mixture wasconcentrated under reduced pressure to afford the title compound asbrown oil.

LC-MS Method1: 0.357 min, MS (m/z): 195.0 (M+H⁺).

[(1R,5S,6r)-6-(5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone

A solution of(1R,5S,6r)-6-(5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (50.0 mg, 0.26 mmol) in Pyridine (2 mL) were added EDCI (49.3mg, 0.26 mmol), 1-isopropylimidazole-4-carboxylic acid (39.7 mg, 0.26mmol). The suspension was stirred at 20° C. for 16 hr. The reactionmixture was quenched with H₂O (10 mL). The residue was extracted withEtOAc (20 mL×3), washed with saturated NaCl (5 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byprep-HPLC (NH₃) and lyophilized to afford compound the title compound(5.77 mg, 6.8% yield) as yellow solid.

LC-MS Method1: 2.693 min, MS (m/z): 331.2 (M+H⁺).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.59 (s, 1H), 7.40 (s, 1H), 4.64(s, 1H), 4.28 (s, 1H), 4.12 (br d, J=12.63 Hz, 1H), 3.86 (br d, J=12.38Hz, 1H), 3.51-3.57 (m, 1H), 2.59-2.65 (m, 1H), 2.44-2.51 (m, 1H), 2.00(br s, 1H), 1.90 (br s, 1H), 1.54-1.61 (m, 3H), 1.46-1.50 (m, 7H), 1.43(d, J=6.63 Hz, 7H), 1.38 (t, J=3.25 Hz, 1H), 1.25 (s, 4H), 1.18 (s, 3H),0.85 (t, J=7.44 Hz, 4H).

Example 42{(1R,5S,6r)-6-[(5R)-5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanoneExample 43{(1R,5S,6r)-6-[(5S)-5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanone

The compounds in Example 42 and 43 were obtained during the course ofthe preparation in Example 41, respectively. They were isolated from thefinal step of Example 41 by SFC purification, which are{(1R,5S,6r)-6-[(5R)-5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanone(63.41 mg, 0.19 mmol, 9.3% yield) and{(1R,5S,6r)-6-[(5S)-5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanone(69.78 mg, 0.21 mmol, 10.2% yield) as white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.66 (s, 1H), 7.48 (s, 1H), 4.74 (br d,J=11.8 Hz, 1H), 4.36 (spt, J=6.7 Hz, 1H), 4.19 (d, J=12.5 Hz, 1H), 3.94(dd, J=4.0, 12.0 Hz, 1H), 3.61 (dd, J=4.1, 12.4 Hz, 1H), 2.74-2.63 (m,1H), 2.60-2.48 (m, 1H), 2.15-2.02 (m, 1H), 2.01-1.90 (m, 1H), 1.66-1.58(m, 2H), 1.50 (d, J=6.8 Hz, 6H), 1.45 (t, J=3.4 Hz, 1H), 1.32 (s, 3H),0.92 (t, J=7.5 Hz, 3H)

Example 44(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanoneethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride

To 6-ethyl 3-(tert-butyl)(1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (3.5 g, 13.71mmol) was added HCl/dioxane (50. mL, 3 mmol). The mixture was stirred at30° C. for 2 h to give brown solution. TLC (PE:EtOAc=5:1) showed a newspot. The reaction mixture was concentrated directly to give the titlecompound (2.5 g, 13.044 mmol, 95.15% yield) as a black solid.

6-ethyl 3-[2-(trimethylsilyl)ethyl](1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate

To a solution of ethyl(1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (2.5 g,13.04 mmol) in DCM (20.27 mL) was added DIPEA (10.78 mL, 65.22 mmol) at0° C. Then 2,5-dioxopyrrolidin-1-yl (2-(trimethylsilyl)ethyl) carbonate(4.06 g, 15.65 mmol) in DCM (20.27 mL) was added to the mixture, whichwas stirred at 30° C. for 12 h to give brown suspension. TLC(PE:EtOAc=3:1) showed a new spot. The reaction mixture was concentrateddirectly. The crude product was purified by flash column (PE to 20%EtOAc in PE) to give the title compound (3.5 g, 11.688 mmol, 89.609%yield) as yellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=4.20-4.10 (m, 4H), 3.73 (d, J=11.2 Hz,1H), 3.65 (d, J=11.2 Hz, 1H), 3.49 (t, J=11.2 Hz, 2H), 2.12 (s, 2H),1.48 (d, J=3.2 Hz, 1H), 1.28 (t, J=6.8 Hz, 3H), 1.00-0.90 (2H), 0.03 (s,9H). 2-(trimethylsilyl)ethyl(1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of 6-ethyl 3-[2-(trimethylsilyl)ethyl](1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (3.5 g, 11.69mmol) in THF (40 mL) was added LiAlH₄ (0.67 g, 17.53 mmol) at 0° C. Themixture was stirred at 0° C. for 20 min to give white suspension. TLC(PE:EtOAc=1:1) showed the reaction was completed. The reaction mixturewas poured into H₂O (0.6 mL), 1N NaOH aq (0.6 mL), H₂O (1.8 ml) andfiltered. The filtrate was concentrated to give yellow oil. The crudeproduct was purified by flash column (PE to 40% EtOAc in PE) to give thetitle compound (1.2 g, 4.662 mmol, 39.885% yield) as colorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=4.15 (dd, J=8.8, 7.6 Hz, 2H), 3.67 (d,J=10.8 Hz, 1H), 3.60 (d, J=10.8 Hz, 1H), 3.60-3.45 (m, 2H), 3.41 (dt,J=8.0, 4.0 H, 2H), 1.50-1.40 (m, 3H), 1.00-0.85 (m, 3H), 0.03 (s, 9H).2-(trimethylsilyl)ethyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of 2-(trimethylsilyl)ethyl(1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(1.2 g, 4.66 mmol) in DCM (15 mL) was added DMP (2.97 g, 6.99 mmol),NaHCO₃ (979.14 mg, 11.66 mmol) at 0° C. The mixture was stirred at 30°C. for 2 h. TLC (PE:EtOAc=1:1) showed the reaction was completed. Thereaction mixture were poured into H₂O (40 mL) and extracted with EtOAc(30 mL×4). The combined organic layers were washed with NaHCO₃.aq. (50mL) and Na₂SO₃.aq. (50 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product was purified by flash column(PE to 30% EtOAc in PE) to give the title compound (0.8200 g, 3.2108mmol, 68.871% yield) as brown oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=9.46 (d, J=4.0 Hz, 1H), 4.17 (dd,J=7.6, 4.0 Hz, 2H), 3.80 (d, J=11.6 Hz, 1H), 3.60 (d, J=11.6 Hz, 1H),3.54 (t, J=11.6 Hz, 2H), 2.24 S, 2H), 1.83 (dd, J=6.4, 3.2 Hz, 1H), 0.99(dd, J=7.6, 4.0 Hz, 2H), 0.03 (s, 9H). 2-(trimethylsilyl)ethyl(1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of 2-(trimethylsilyl)ethyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (820 mg,3.21 mmol) in EtOH (10 mL) were added KOAc (315.11 mg, 3.21 mmol), HOAc(0.18 mL, 3.21 mmol), NH₂OH.HCl (0.17 mL, 4.17 mmol). The mixture wasstirred at 25° C. for 3 h to give white suspension. TLC (PE:EtOAc=2:1)showed the reaction was completed. The reaction mixture was removedunder reduced pressure. H₂O (40 mL) was added to the residue and themixture was extracted with EtOAc (30 mL×4). The combined organic phaseswere washed with saturated sodium hydrogen carbonate (30 mL×2) andsaturated brine (40 mL×2) and dried over Na₂SO₄. The solvent was removedunder reduced pressure to give the title compound (850 mg, 3.1435 mmol,97.904% yield) as brown oil.

2-(trimethylsilyl)ethyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of 2-(trimethylsilyl)ethyl(1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(850 mg, 3.14 mmol) in DMF (9 mL) was added NCS (503.7 mg, 3.77 mmol).The mixture was stirred at 25° C. for 3 h to give brown solution. TLC(PE:EtOAc=2:1) showed the reaction was completed. The reaction mixturewas poured into H₂O (40 mL) and extracted with EtOAc (30 mL×4). Thecombined organic layers were washed with brine (50 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by flash column (PE to 30% EtOAc in PE) to give thetitle compound (750 mg, 2.4602 mmol, 78.264% yield) as colorless oil.

2-(trimethylsilyl)ethyl(1R,5S,6r)-6-[5-(chloromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of 2-(trimethylsilyl)ethyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(400 mg, 1.31 mmol) in DMF (5.3333 mL) were added 3-chloroprop-1-ene(0.54 mL, 6.56 mmol) and Et₃N (0.51 mL, 3.94 mmol). The mixture wasstirred at 25° C. for 12 h to give brown solution. TLC (PE:EtOAc=3:1)showed the reaction was completed. H₂O (40 mL) was added to the mixture,which was extracted with EtOAc (30 mL×4). The combined organic phaseswere washed with saturated brine (40 mL×2) and dried over Na₂SO₄. Thesolvent was removed under reduced pressure. The crude product waspurified by flash column (PE to 20% EtOAc in PE) to give the titlecompound (160 mg, 0.4639 mmol, 35.354% yield) as colorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) 5=4.85-4.75 (m, 1H), 4.16 (dd, J=9.2, 7.2Hz, 2H), 3.76 (d, J=11.2 Hz, 1H), 3.70 (d, J=11.2 Hz, 1H), 3.61 (dd,J=7.2, 4.0 Hz, 1H), 3.55-3.40 (m, 3H), 3.15-3.05 (m, 1H), 2.95-2.80 (m,1H), 52.00 (brs, 2H), 1.50 (brs, 1H), 1.00 (dd, J=9.2, 7.2 Hz, 2H), 0.05(s, 9H).

4-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-2-oxa-3-azabicyclo[3.1.0]hex-3-ene

To a solution of 2-(trimethylsilyl)ethyl(1R,5S,6r)-6-[5-(chloromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(20 mg, 0.06 mmol) in DMSO (1 mL) was added t-BuOK (13.01 mg, 0.12mmol). The mixture was stirred at 20° C. for 30 min to give brownsolution. The reaction mixture was lyophilized directly to give thetitle compound (8 mg, 0.0487 mmol, 84.022% yield) as brown solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=4.90-4.80 (m, 1H), 4.04 (d, J=12.4 Hz,1H), 3.80-3.60 (m, 2H), 3.40-3.30 (m, 1H), 2.40-2.30 (m, 1H), 2.20-1.90(m, 2H), 1.60-1.50 (m, 1H), 1.00-0.85 (m, 2H), 0.40-0.30 (m, 1H).(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of4-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-2-oxa-3-azabicyclo[3.1.0]hex-3-ene(30 mg, 0.18 mmol) and 1-isopropylimidazole-4-carboxylic acid (27.75 mg,0.18 mmol) in Pyridine (2.9557 mL) was added EDCI (44.86 mg, 0.23 mmol).The mixture was stirred at 25° C. for 3 h to give yellow solution. LCMSshowed the desire MS as a major peak. The reaction mixture wasconcentrated directly. The residue was purified by prep-HPLC (NH₃) togive the title compound (7.58 mg, 0.0252 mmol, 14.02% yield) as yellowsolid.

LC-MS Method1: 301.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.68 (1H, d, J=1.51 Hz), 7.48 (1H,d, J=1.25 Hz), 4.85 (1H, td, J=5.33, 2.13 Hz), 4.78 (1H, br d, J=10.79Hz), 4.36 (1H, m, J=13.49, 6.68 Hz), 4.23 (1H, br d, J=11.80 Hz), 3.98(1H, br dd, J=12.05, 4.52 Hz), 3.60-3.70 (1H, m), 2.36 (1H, dt, J=8.85,4.49 Hz), 1.98-2.15 (2H, m), 1.66 (1H, br d, J=3.51 Hz), 1.51 (6H, d,J=6.78 Hz), 0.85-0.89 (1H, m), 0.31 (1H, br s)

Example 45(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone2-(trimethylsilyl)ethyl(1R,5S,6r)-6-[5-(chloromethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of 2-(trimethylsilyl)ethyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(150 mg, 0.49 mmol) in DMF (2 mL) were added 3-chloro-2-methylprop-1-ene(0.24 mL, 2.46 mmol) and Et₃N (0.19 mL, 1.48 mmol). The mixture wasstirred at 25° C. for 12 h to give brown mixture. The reaction mixturewas poured into H₂O (10 mL) and extracted with EtOAc (15 mL×4). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thetitle compound (150 mg, 0.4179 mmol, 84.931% yield) as brown oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=4.25-4.10 (m, 2H), 3.80-3.60 (m, 2H),3.55-3.45 (m, 4H), 3.05 (d, J=9.2 Hz, 1H), 2.65 (d, J=9.2 Hz, 1H),2.00-1.90 (m, 1H), 1.55-1.45 (m, 2H), 1.05 (s, 3H), 1.50-1.40 (m, 1H),0.99 (t, J=8.0 Hz, 2H), 0.04 (s, 9H).4-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-ene

To a solution of 2-(trimethylsilyl)ethyl(1R,5S,6r)-6-[5-(chloromethyl)-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(130 mg, 0.36 mmol) in DMSO (4 mL) was added t-BuOK (81.28 mg, 0.72mmol). The mixture was stirred at 20° C. for 30 min to give brownsolution. The reaction mixture was lyophilized directly to give thetitle compound (60 mg, 0.3366 mmol, 92.95% yield) as brown solid.

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of4-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-ene(60 mg, 0.34 mmol) and 1-isopropylimidazole-4-carboxylic acid (51.9 mg,0.34 mmol) in Pyridine (5 mL) was added EDCI (129.07 mg, 0.67 mmol). Themixture was stirred at 25° C. for 3 h to give yellow solution. Themixture was concentrated directly. The residue was purified by prep-HPLC(NH₃). The afforded solid was purified by prep-TLC (DCM:MeOH=15:1) togive the title compound (11.96 mg, 0.0380 mmol, 11.301% yield) as lightyellow solid.

LC-MS Method1: 315.2 [M+H⁺]

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.67 (1H, s), 7.48 (1H, s), 4.75(1H, br d, J=12.05 Hz), 4.36 (1H, m, J=13.43, 6.84 Hz), 4.22 (1H, br d,J=12.30 Hz), 3.97 (1H, br d, J=12.05 Hz), 3.64 (1H, br d, J=12.30 Hz),2.08 (2H, br d, J=3.76 Hz), 2.01 (1H, br s), 1.67 (3H, s), 1.51 (6H, d,J=6.78 Hz), 0.90 (1H, dd, J=9.41, 5.14 Hz), 0.33-0.43 (1H, m)

Example 46(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonetert-butyl(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of Et₃N (0.36 mL, 2.18 mmol) and 2-methylbut-2-ene (1.16mL, 10.92 mmol) in THE was added tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 0.73 mmol). The mixture was stirred at 20° C. for 16 hr. Themixture was diluted with H₂O (15 mL) and extracted with EtOAc (15 mL×3).The organic phase was washed with brine (50 mL), dried over anhydrousNa₂SO₄ and concentrated to give a residue. The residue was purified byflash column (PE:EtOAc=1:0-0:1) to afford the title compound (100 mg,0.3397 mmol, 46.663% yield) as a yellow oil.

(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt

A mixture of tert-butyl(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(160 mg, 0.54 mmol) in TFA (0.5 mL, 0.54 mmol) and DCM (2 mL) wasstirred at 20° C. for 40 min. The reaction mixture was concentrated invacuum and then lyophilized to give the title compound (100 mg, crudeproduct) as yellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.60-3.40 (m, 4H), 2.30-2.20 (m, 2H),2.00-1.70 (m, 2H), 1.24 (s, 3H), 1.15 (s, 3H), 0.95 (d, J=7.6 Hz, 3H).(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of 1-isopropylimidazole-4-carboxylic acid (39.68 mg, 0.26mmol) in DMF (1 mL) were added HATU (127.91 mg, 0.33 mmol) and DIPEA(0.21 mL, 1.29 mmol). The mixture was heated at 50° C. for 30 min.(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (50 mg, 0.26 mmol) was added the mixture. The resulting mixturewas stirred at 20° C. for 4 hr. The reaction mixture was diluted withH₂O (10 mL) and extracted with EtOAc (10 mL×2), then washed with brine(10 mL). The combined organic layers were separated, then dried overNa₂SO₄ and concentrated in vacuum to give crude oil. The crude oil waspurified by prep-HPLC (NH₃) and lyophilized to give the title compound(6 mg, 0.0182 mmol, 7.0554% yield) as white solid.

¹H NMR (400 MHz, DMSO) δ=7.98 (d, J=2.8 Hz, 2H), 4.79 (br d, J=12.5 Hz,1H), 4.65 (td, J=6.8, 13.2 Hz, 1H), 4.17-4.10 (m, 1H), 4.01 (br d,J=13.1 Hz, 1H), 3.65 (br s, 1H), 3.02 (br d, J=6.5 Hz, 1H), 2.30-2.07(m, 2H), 1.60 (d, J=6.5 Hz, 6H), 1.47 (br s, 1H), 1.48-1.45 (m, 1H),1.40 (s, 3H), 1.31 (s, 3H), 1.22 (d, J=7.5 Hz, 3H)

Example 47(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4S)-4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanoneExample 48(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4R)-4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone

To a solution of 1-isopropylimidazole-4-carboxylic acid (476.15 mg, 3.09mmol) in Pyridine (8 mL) were added EDCI (592.06 mg, 3.09 mmol) and(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane(400 mg, 2.06 mmol). The resulting mixture was stirred at 20-25° C. for2 h. LCMS showed the desired MS (as a major peak). The reaction mixturewas concentrated directly. The residue was purified by prep-HPLC (NH₃).The afforded flows were combined, concentrated to remove most of CH₃CNand lyophilized. The product was chirally separated by SFC andlyophilized to afford(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4S)-4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone(48.84 mg, 0.15 mmol, 7.2% yield) and(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4R)-4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone(52.66 mg, 0.1594 mmol, 7.7403% yield) both as yellow gum.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (br s, 1H), 7.49 (s, 1H),4.85-4.64 (m, 1H), 4.48-4.29 (m, 1H), 4.27-4.12 (m, 1H), 4.03-3.88 (m,1H), 3.71-3.54 (m, 1H), 2.78 (quin, J=7.2 Hz, 1H), 2.30-1.95 (m, 2H),1.65 (br s, 3H), 1.52 (s, 6H), 1.31 (d, J=2.8 Hz, 3H), 1.28-1.18 (m,4H), 1.10 (br d, J=7.3 Hz, 3H)

Example 49(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

tert-butyl (1R,5S,6s)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylateTo a solution of tert-butyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2000 mg,9.47 mmol) in MeOH (8 mL) were added K₂CO₃ (2616.87 mg, 18.93 mmol) and1-diazo-1-dimethoxyphosphoryl-propan-2-one (1818.71 mg, 9.47 mmol). Thereaction mixture was stirred at 20° C. for 16 hr to give a light yellowmixture. TLC (PE/EtOAc=3:1) showed a new spot. The reaction mixture wasdiluted with H₂O (300 mL) and extracted with EtOAc (100 mL×2). Theorganic layer was washed with brine (100 mL×2) and dried over anhydroussodium sulfate to give a residue. The residue was purified by silicacolumn (PE/EtOAc=3:1) to give the title compound (1800 mg, 8.6843 mmol,91.733% yield) as white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.35 (d, J=11.2 Hz, 1H), 3.57 (d,J=11.2 Hz, 1H), 3.36-3.30 (m, 2H), 1.88 (s, 1H), 1.84-1.80 (m, 2H), 1.42(s, 9H), 1.12-1.09 (m, 1H). tert-butyl(1R,5S,6s)-6-(3-hydroxy-3-methyl-1-butyn-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6s)-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (1800 ng,8.68 mmol) in THF (90 mL) was added n-BuLi (0.2 mL, 9.55 mmol) at −78°C. The reaction mixture was stirred for 30 min at −78° C. The acetone(1109.65 mg, 19.11 mmol) was added to the reaction mixture. Then thereaction mixture was stirred at 25° C. for 16 hr to give a yellowmixture. The reaction mixture was quenched with H₂O (100 mL) andextracted with EtOAc (100 mL×2). The organic layer was washed with brine(100 mL) and dried over anhydrous sodium sulfate to give a residue. Theresidue was purified by silica column (PE/EtOAc=3:1) to give the titlecompound as white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.63 (d, J=11.2 Hz, 1H), 3.55 (d,J=11.2 Hz, 1H), 3.40-3.10 (m, 2H), 1.83 (s, 1H), 1.78-1.60 (m, 2H), 1.47(s, 6H), 1.42 (s, 9H), 1.10-1.09 (m, 1H). tert-butyl(1R,5S,6r)-6-(5,5-dimethyl-2-oxido-4-oxo-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6s)-6-(3-hydroxy-3-methyl-1-butyn-1-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(900 mg, 3.39 mmol) in MeCN (36 mL) were added t-BuONO (699.11 mg, 6.78mmol) and Pd(OAc)₂ (152.3 mg, 0.68 mmol). The reaction mixture wasstirred at 25° C. for 16 hr to give a yellow mixture. TLC (PE/EtOAc=3:1)showed a new spot. The reaction mixture was diluted with H₂O (200 mL)and extracted with EtOAc (100 mL×2). The organic layer was washed withbrine (200 mL), filtered and dried over anhydrous sodium sulfate to givea residue. The residue was purified by silica column (PE/EtOAc=3:1) togive the title compound (600 mg, 1.9333 mmol, 57% yield) as yellowsolid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.72 (d, J=11.2 Hz, 1H), 3.65 (d,J=11.2 Hz, 1H), 3.47-3.40 (m, 2H), 2.40-2.20 (m, 2H), 1.60 (s, 1H), 1.49(s, 6H), 1.44 (s, 9H). tert-butyl(1R,5S,6r)-6-(4-hydroxy-5,5-dimethyl-2-oxido-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-(5,5-dimethyl-2-oxido-4-oxo-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(650 mg, 2.09 mmol) in THF (10 mL) was added a solution of NaBH₄ (87.15mg, 2.3 mmol) in MeOH (3 mL) at 0° C. The reaction mixture was stirredat 0° C. for 2 hr to give a white mixture. The reaction mixture wasquenched with H₂O (100 mL) and extracted with EtOAc (100 mL×2). Theorganic layer was dried over anhydrous sodium sulfate to give the titlecompound (570 mg, 1.8248 mmol, 87.128% yield) as colorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=4.25 (d, J=11.2 Hz, 1H), 4.20 (d,J=11.2 Hz, 1H), 3.70-3.50 (m, 2H), 3.50-3.40 (m, 2H), 2.25-2.15 (m, 1H),2.15-2.00 (m, 1H), 1.70 (d, J=3.2 Hz, 1H), 1.43 (s, 9H), 1.43 (s, 3H),1.35 (s, 3H). tert-butyl(1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-2-oxido-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-(4-hydroxy-5,5-dimethyl-2-oxido-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(400 mg, 1.28 mmol) in THF (20 mL) was added NaH (36.88 mg, 1.54 mmol)at 0° C. and stirred at 0° C. for 0.5 hr to give a yellow mixture. MeI(0.11 mL, 1.79 mmol) was added to the reaction mixture. The reactionmixture was stirred at 20° C. for 16 hr to give a light yellow mixture.TLC (PE/EtOAc=1:1) showed a new spot. The reaction mixture was quenchedwith H₂O (100 mL) and extracted with EtOAc (50 mL×3). The organic layerwas concentrated to give a residue. The residue was purified by silicacolumn (PE/EtOAc=1:1) to give the title compound (380 mg, 1.1643 mmol,90.916% yield) as colorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=4.02 (d, J=4.0 Hz, 1H), 3.80-3.60 (m,2H), 3.50-3.35 (m, 2H), 3.41 (s, 3H), 2.15-2.00 (m, 2H), 1.69 (s, 1H),1.43 (s, 9H), 1.39 (s, 3H), 1.37 (s, 3H). tert-butyl(1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A solution of tert-butyl(1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-2-oxido-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(380 mg, 1.16 mmol) in P(MeO)₃ (1. mL, 1.16 mmol) was stirred at 110° C.for 16 hr to give a yellow mixture. TLC (PE/EtOAc=1:1) showed a newspot. The reaction mixture was diluted with EtOAc (200 mL) and washedwith H₂O (100 mL×3). The organic layer was concentrated to give aresidue. The residue was purified by silica column (PE/EtOAc=1:1) togive the title compound (320 mg, 1.031 mmol, 88.551% yield) as colorlessoil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=4.01 (d, J=11.2 Hz, 1H), 3.80-3.60 (m,2H), 3.46 (s, 3H), 3.46-3.30 (m, 2H), 2.20-2.00 (m, 2H), 1.64 (s, 1H),1.46 (s, 9H), 1.35 (s, 3H), 1.29 (s, 3H).(1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 0.64 mmol) in DCM (4 mL) was added TFA (0.8 mL, 0.64 mmol). Thereaction mixture was stirred at 25° C. for 1 hr to give a colorlessmixture. The reaction mixture was removed the solvent to give a residue.The residue was used for the next step directly.

LC-MS Method1 0.323 min, MS (m/z) 211.0 (M+H⁺).

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 1-isopropylimidazole-4-carboxylic acid (49.12 mg, 0.32mmol), HATU (91.62 mg, 0.48 mmol) in DMF (2.393 mL) was added DIPEA(0.16 mL, 0.96 mmol). The reaction mixture was stirred at 15° C. for 30min. Then(1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (67 mg, 0.32 mmol) was added to the reaction. The reactionmixture was stirred at 15° C. for 0.5 hr to give a yellow mixture. LCMSshowed the desired MS. The reaction mixture was purified by prep-HPLC(NH₃) to give the title compound (65.26 mg, 0.1884 mmol, 59.122% yield)as white powder

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.67 (s, 1H), 7.47 (s, 1H), 4.75 (dd,J=12.0, 16.8 Hz, 1H), 4.35 (m, 1H), 4.21 (m, 1H), 4.05-3.92 (m, 2H),3.66-3.58 (m, 1H), 2.25-2.17 (m, 1H), 2.07 (m, 1H), 1.50 (d, J=6.8 Hz,6H), 1.47 (m, 1H), 1.35 (s, 3H), 1.28 (d, J=4.4 Hz, 3H)

Example 50[(1R,5S,6r)-6-(4-isobutyl-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanonetert-butyl(1R,5S,6r)-6-(4-isobutyl-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 0.77 mmol) and Et₃N (0.3 mL, 2.3 mmol) in DMF (2.8571 mL) wasadded 2,5-dimethylhex-2-ene (258.23 mg, 2.3 mmol). The mixture wasstirred at 25° C. for 12 h. LCMS showed the desired mass was detected.The reaction mixture was poured into H₂O (50 mL), extracted by EtOAc (40mL×3). The organic phase was washed with H₂O (30 mL×3) and brine (50mL), dried over anhydrous Na₂SO₄, concentrated to give the titlecompound (150 ng, 58.1% yield) as colorless oil.

(1R,5S,6r)-6-(4-isobutyl-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt

The solution of tert-butyl(1R,5S,6r)-6-(4-isobutyl-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(150 mg, 0.45 mmol) in HCl/Dioxane (10. mL, 0.45 mmol) was stirred at15° C. for 1 h. TLC (PE:EtOAc=3:1) showed the starting material (Rf=0.3)was consumed completely and a new spot (Rf=0) was found. LCMS showed thedesired MS. The reaction mixture was concentrated under reduced pressureto give the title compound (105 mg, 0.3110 mmol, 69.757% yield, crude)as a white solid. The crude product was used directly for next step.

LC-MS Method1 0.725, MS (m/z) 237.1 (M+H⁺).

[(1R,5S,6r)-6-(4-isobutyl-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone

To a solution of(1R,5S,6r)-6-(4-isobutyl-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (105 mg, 0.44 mmol) and DIPEA (0.22 mL, 1.33 mmol) in DMF (3mL) were added HATU (202.58 mg, 0.53 mmol) and1-isopropylimidazole-4-carboxylic acid (68.49 mg, 0.44 mmol). Themixture was stirred at 20° C. for 12 h. LCMS showed the desired mass wasdetected. The reaction mixture was poured into H₂O (30 mL), extracted byEtOAc (20 mL×3). The organic phase was washed by brine, dried overanhydrous Na₂SO₄ and concentrated to give a residue. The residue waspurified by prep-HPLC (NH₃) to give the title compound (4.86 mg, 0.0130mmol, 2.9368% yield) as an off-white solid.

LC-MS Method1: 372.0 [M+H⁺]

¹H NMR (400 MHz, METHANOL-d₄) δ=9.11 (s, 1H), 8.21 (br s, 1H), 4.77-4.69(m, 2H), 4.13-4.00 (m, 3H), 3.72 (br dd, J=4.4, 12.4 Hz, 1H), 3.01-2.92(m, 1H), 2.36-2.25 (m, 1H), 2.20-2.06 (m, 1H), 1.79-1.71 (m, 1H), 1.63(d, J=6.8 Hz, 6H), 1.36 (d, J=2.4 Hz, 3H), 1.21 (s, 3H), 0.97 (br d,J=6.5 Hz, 6H), 0.90-0.87 (m, 3H)

Example 51(1-cyclopropyl-11H-imidazol-4-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

(1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To the mixture of6-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-enehydrochloride (49.0 mg, 0.27 mmol) in Pyridine (1.5 mL) were added EDCI(52.7 mg, 0.27 mmol) and 1-cyclopropylimidazole-4-carboxylic acid (41.83mg, 0.27 mmol). The suspension was stirred at 20° C. for 16 hr. Thesolution was purified by prep-HPLC (NH₃) and lyophilized to afford thetitle compound (6.79 mg, 7.9% yield) as yellow solid.

LC-MS Method1: 2.058 min, MS (m/z): 313.2 (M+H⁺).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.56 (d, J=1.38 Hz, 1H) 7.43 (d,J=1.25 Hz, 1H) 4.63 (d, J=12.01 Hz, 1H) 4.12 (d, J=12.38 Hz, 1H) 3.87(dd, J=11.82, 3.94 Hz, 1H) 3.55 (dd, J=12.88, 4.38 Hz, 1H) 3.26-3.33 (m,1H) 2.89 (s, 2H) 2.05 (br d, J=3.50 Hz, 1H) 1.93-1.99 (m, 1H) 1.45 (brd, J=3.63 Hz, 1H) 1.18 (s, 3H) 1.02-1.07 (m, 2H) 0.95-0.99 (m, 3H)0.90-0.94 (m, 2H) 0.61-0.66 (m, 2H)

Example 52[1-(1-methylcyclopropyl)-1H-imidazol-4-yl][(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone[1-(1-methylcyclopropyl)-1H-imidazol-4-yl][(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylic acid(37.3 mg, 0.22 mmol) in DMF (1.5 mL) were added HATU (110.87 mg, 0.29mmol) and Et₃N (0.09 mL, 0.67 mmol). The mixture was stirred at 20-25°C. for 0.5 h. To the mixture was added6-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-enehydrochloride (40 mg, 0.22 mmol). The resulting mixture was stirred for2 h. The residue was purified by prep-HPLC (NH₃). The afforded flowswere combined, concentrated to remove most of CH₃CN and lyophilized toafford the title compound (11.21 mg, 0.0343 mmol, 15.303% yield) as ayellow solid.

LC-MS Method1: 327.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.69 (d, J=1.3 Hz, 1H), 7.53 (d, J=1.3Hz, 1H), 4.73 (br d, J=12.0 Hz, 1H), 4.21 (br d, J=12.3 Hz, 1H), 3.95(br dd, J=4.0, 12.0 Hz, 1H), 3.62 (br dd, J=4.0, 12.5 Hz, 1H), 2.97 (s,2H), 2.13 (br d, J=3.5 Hz, 1H), 2.07-2.01 (m, 1H), 1.58 (s, 3H), 1.53(t, J=3.4 Hz, 1H), 1.18-1.08 (m, 4H), 0.98-0.89 (m, 2H), 0.75-0.68 (m,2H)

Example 53(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(1S,5S)-1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanoneExample 54(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(1R,5R)-1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone

The compound produced in Example 45 was applied for SFC chiralseparation to afford(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(1S,5S)-1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone(22.30 mg), and(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(1R,5R)-1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone(21.47 mg) as white solid.

(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(1S,5S)-1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanoneLC-MS Method1: 315.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.67 (1H, s), 7.48 (1H, s), 4.75(1H, br d, J=12.05 Hz), 4.36 (1H, m, J=13.43, 6.84 Hz), 4.22 (1H, br d,J=12.30 Hz), 3.97 (1H, br d, J=12.05 Hz), 3.64 (1H, br d, J=12.30 Hz),2.08 (2H, br d, J=3.76 Hz), 2.01 (1H, br s), 1.67 (3H, s), 1.51 (6H, d,J=6.78 Hz), 0.90 (1H, dd, J=9.41, 5.14 Hz), 0.33-0.43 (1H, m)

(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(1R,5R)-1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone

LS-MS method1: 315.2 [M+H⁺]¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.67 (1H, s), 7.48 (1H, s), 4.75(1H, br d, J=12.05 Hz), 4.36 (1H, m, J=13.43, 6.84 Hz), 4.22 (1H, br d,J=12.30 Hz), 3.97 (1H, br d, J=12.05 Hz), 3.64 (1H, br d, J=12.30 Hz),2.08 (2H, br d, J=3.76 Hz), 2.01 (1H, br s), 1.67 (3H, s), 1.51 (6H, d,J=6.78 Hz), 0.90 (1H, dd, J=9.41, 5.14 Hz), 0.33-0.43 (1H, m)

Example 55(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5-methyl-4-phenyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonetert-butyl(1R,5S,6r)-6-(4-bromo-5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-(5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(2.46 g, 9.31 mmol, from Example 56) in DMF (25 mL) was added NBS (1.66g, 9.31 mmol) at 0 to 5° C. The reaction was stirred at 15° C. for 5hours to give a yellow solution. LCMS showed the reaction was completed.The reaction was diluted with H₂O (150 mL) and extracted with EA (40mL×3). The combined organic layers were washed with NH₄Cl aq. (40 mL×2),NaHCO₃ aq. (40 mL) and brine (40 mL), dried over Na₂SO₄, filtered andconcentrated to afford the title compound (2.9 g, 90.786% yield) aslight yellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ 3.75-3.60 (m, 2H), 3.55-3.40 (m, 2H),2.38 (s, 3H), 2.20-2.00 (m, 2H), 1.70-1.65 (m, 1H), 1.46 (s, 9H).tert-butyl(1R,5S,6r)-6-(5-methyl-4-phenyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A mixture of tert-butyl(1R,5S,6r)-6-(4-bromo-5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.29 mmol), phenylboronic acid (42.63 mg, 0.35 mmol) and NaHCO₃(73.43 mg, 0.87 mmol) in DMF (1.5 mL) and H₂O (0.2 mL) was purged withN₂. Then, Pd(dppf)Cl₂ (21.32 mg, 0.03 mmol) was added and the mixturewas purged with N₂ and heated at 90° C. under N₂ atmosphere for 12 h togive black mixture. The mixture was diluted with EtOAc (20 mL) and H₂O(10 mL). The solid was filtered off. The organic layer was washed withH₂O (10 mL) and brine (10 mL), then, dried over Na₂SO₄ and concentratedin vacuum to give brown oil. The brown oil was purified by prep-TLC(PE/EtOAc=6/1) to give the title compound (50 mg, 0.1469 mmol, 50.411%yield) as a white solid.

LC-MS Method1 0.943 min, MS (m/z) 340.9 (M+H⁺).

(1R,5S,6r)-6-(5-methyl-4-phenyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride

A mixture of tert-butyl(1R,5S,6r)-6-(5-methyl-4-phenyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(50 mg, 0.15 mmol) in 4M HCl/dioxane (5. mL, 0.15 mmol) was stirred at0° C. for 50 min to give colorless solution. The reaction wasconcentrated in vacuum to give the title compound (50 mg, 0.1807 mmol,123% yield) as pale yellow gum, which was used directly in the nextstep.

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5-methyl-4-phenyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 1-isopropylimidazole-4-carboxylic acid (36.21 mg, 0.23mmol) in DMF (2 mL) were added HATU (82.88 mg, 0.22 mmol), Et₃N (0.06mL, 0.45 mmol) and(1R,5S,6r)-6-(5-methyl-4-phenyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (50 mg, 0.18 mmol) at 20° C. The reaction was stirred at20° C. for 4 h to give pale brown solution. The reaction wasconcentrated in vacuum to give pale brown gum, which was purified byprep-HPLC (NH₃). The fluent was concentrated and lyophilized to give thetitle compound (32.53 mg, 0.0864 mmol, 47.831% yield) as pale yellowsolid.

LC-MS Method1: 377.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.57 (d, J=1.3 Hz, 1H), 7.40-7.33 (m,3H), 7.28 (d, J=7.4 Hz, 1H), 7.25-7.21 (m, 2H), 4.59 (d, J=12.1 Hz, 1H),4.26 (spt, J=6.8 Hz, 1H), 4.07 (d, J=12.6 Hz, 1H), 3.96 (dd, J=4.4, 11.9Hz, 1H), 3.62 (dd, J=4.2, 12.6 Hz, 1H), 2.33 (s, 3H), 2.32-2.28 (m, 1H),2.13-2.06 (m, 1H), 1.53-1.53 (m, 1H), 1.41 (d, J=6.6 Hz, 6H)

Example 56(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonetert-butyl(1R,5S,6r)-6-(5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(0.5 g, 1.92 mmol) and prop-1-en-2-yl acetate (1.04 mL, 9.59 mmol) inDCM (6 mL) was added Et₃N (0.8 mL, 5.75 mmol) drop-wise at 0° C. Thereaction was then stirred at 20° for 12 h to give pale yellow solution.LCMS showed the desired MS. The solution was diluted with DCM (30 mL)and washed with H₂O (15 mL×2), saturated NaHCO₃ (15 mL) and brine (15mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuumto give the title compound (460 mg, 1.7403 mmol, 90.747% yield) as paleyellow oil, which was used directly in the next step.

(1R, 5S, 6r)-6-(5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane TFAsalt

To a solution of tert-butyl(1R,5S,6r)-6-(5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(235 mg, 0.89 mmol) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid(1. mL, 13.06 mmol). The reaction mixture was stirred at 20° C. for 3 hrto give a yellow solution. The reaction mixture was evaporated in vacuumto give the title compound (260 mg, 0.9345 mmol, 105.11% yield) asyellow oil. It used directly in the next step.

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

A 100 mL round-bottom flask was charged with1-isopropylimidazole-4-carboxylic acid (70 mg, 0.45 mmol),N-ethyl-N-isopropylpropan-2-amine (0.24 mL, 1.41 mmol), HATU (190.94 mg,0.50 mmol) and DMF (3 mL). After stirring for 30 min,(1R,5S,6r)-6-(5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane TFAsalt (126.33 mg, 0.45 mmol) was added. The reaction mixture was stirredat 20° C. for 16 hr to give a yellow solution. H₂O (30 mL) was added andit was extracted with EtOAc (30 mL×2). The combined organic layer wasdried over Na₂SO₄ and concentrated in vacuum to give a yellow oil. Thecrude was purified by prep-HPLC (NH₃). The afforded flows wereconcentrated in vacuum to remove most of CH₃CN and lyophilized to givethe title compound (13.06 mg, 0.0383 mmol, 8.4313% yield) as whitesolid.

LC-MS Method1: 301.1 [M+H⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 9.22 (br s, 1H), 8.35 (s, 1H), 6.07 (s, 1H),4.66 (td, J=6.64, 13.35 Hz, 1H), 4.11 (br d, J=10.76 Hz, 1H), 4.02 (brd, J=12.63 Hz, 1H), 3.98 (br dd, J=4.06, 10.82 Hz, 1H), 3.63 (br dd,J=4.19, 12.57 Hz, 1H), 2.34 (s, 3H), 2.14-2.20 (m, 1H), 2.05-2.10 (m,1H), 1.84 (t, J=3.38 Hz, 1H), 1.51 (d, J=6.63 Hz, 6H)

Example 57[(1R,5S,6r)-6-(1,2-benzoxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanoneN-phenoxyacetamide

To a solution of (aminooxy)benzene (200 mg, 1.37 mmol) in THF (3 mL) wasadded Ac₂O (280.49 mg, 2.75 mmol) at 0° C. The mixture was stirred at20° C. for 3 h to give brown suspension. The reaction mixture wasconcentrated directly. The crude product was purified by flash column(PE to 20% EtOAc in PE) to give the title compound (170 mg, 1.1246 mmol,81.868% yield) as white solid.

¹H NMR (400 MHz, DMSO-d6) δ=11.67 (brs, 1H), 7.35-7.25 (m, 2H),7.05-6.95 (m, 3H), 1.92 (s, 3H).

tert-butyl(1R,5S,6r)-6-(1,2-benzoxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of N-phenoxyacetamide (50 mg, 0.33 mmol) in tert-Amylalcohol (1.5 mL, 0.33 mmol) were added Pd(TFA)₂ (9.92 mg, 0.03 mmol),tert-butyl 6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (139.76 mg,0.66 mmol) and TBHP (0.17 mL, 0.83 mmol). The mixture was stirred at 60°C. under N₂ for 12 h to give brown solution. The reaction mixture waspoured into NaHSO₃ aq. (20 mL) and extracted with EtOAc (20 mL×4). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-TLC (PE:EtOAc=6:1) to give the title compound (20mg, 0.0666 mmol, 20.131% yield) as white gum.

3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-1,2-benzoxazole hydrochloride

To a solution of tert-butyl(1R,5S,6r)-6-(1,2-benzoxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(20 mg, 0.07 mmol) was added HCl/dioxane (2.0 mL, 8 mmol). The mixturewas stirred at 20° C. for 1 h to give colorless solution. TLC(PE:EtOAc=5:1) showed the reaction was completed. The reaction mixturewas concentrated directly to give the title compound (15 mg, 0.0634mmol, 95.168% yield) as brown gum.

[(1R,5S,6r)-6-(1,2-benzoxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone

To a solution of 1-isopropylimidazole-4-carboxylic acid (22.08 mg, 0.14mmol) in DMF (1.5 mL) were added HATU (43.79 mg, 0.11 mmol), IEA (0.06mL, 0.38 mmol) and3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-1,2-benzoxazole hydrochloride(30 mg, 0.10 mmol). The mixture was stirred at 20° C. for 1 h to givebrown solution. LCMS showed the desire MS and a part of3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-1,2-benzoxazole hydrochloridewas remained. The mixture was stirred at 20° C. for 12 h to give brownsolution. LCMS showed the desire MS as major peak. The mixture waspoured into H₂O (15 mL) and extracted with EtOAc (15 mL×5). The combinedorganic layer was washed with brine (50 mL), dried over Na₂SO₄ andconcentrated to dryness. The residue was purified by prep-TLC(MeOH:EtOAc=1:11) and the afforded solid was triturated with MTBE (2 mL)and dried in air to give as brown solid. The residue was purified byprep-HPLC (NH₃). The afforded flows were combined, concentrated toremove most of CH3CN and lyophilized to give the title compound (10 mg,0.0297 mmol, 31.14% yield) as white solid.

LC-MS Method1: 336.9 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.73 (1H, d, J=1.25 Hz), 7.68 (1H,d, J=8.03 Hz), 7.47-7.57 (3H, m), 7.31 (1H, dd, J=7.91, 3.89 Hz), 4.91(1H, br d, J=12.05 Hz), 4.34-4.40 (2H, m), 4.08 (1H, br dd, J=12.05,3.76 Hz), 3.74 (1H, br dd, J=12.55, 4.02 Hz), 2.45-2.53 (1H, m),2.31-2.41 (1H, m), 2.07 (1H, t, J=3.26 Hz), 1.53 (6H, d, J=6.53 Hz)

Example 58[(1R,5S,6r)-6-(4-cyclopropyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanoneN-cyclopropyl-2-propanimine

To a solution of cyclopropylamine (0.24 mL, 3.5 mmol) and acetone(1017.34 mg, 17.52 mmol) in DMF (2.5 mL) was added 4A MS (2000 mg, 3.5mmol). The mixture was stirred at 110° C. for 4 hr without monitor. Themixture was filtered to give the title compound (2000 mg, 2.0585 mmol,58.759% yield). The crude product was used directly for next step.

tert-butyl(1R,5S,6r)-6-(4-cyclopropyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of Et₃N (0.36 mL, 2.18 mmol) andN-cyclopropyl-2-propanimine (5000 mg, 5.15 mmol) was added tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 0.73 mmol). The mixture was stirred at 20° C. for 16 hr. LCMSshowed the desired mass. The mixture was diluted with H₂O (50 mL) andextracted by EtOAc (30 mL×2). The organic phase was washed with brine(50 mL), dried over anhydrous Na₂SO₄ and concentrated to give a residue.The residue was purified by flash column (PE:EtOAc=1:0-0:1) to affordthe title compound (80 mg, 0.2489 mmol, 34.192% yield) as a yellow oil

¹H NMR (400 MHz, DMSO-d6) δ=11.67 (brs, 1H), 7.35-7.25 (m, 2H),7.05-6.95 (m, 3H), 1.92 (s, 3H).

(1R,5S,6r)-6-(4-cyclopropyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-(4-cyclopropyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(80 mg, 0.25 mmol) in DCM (4.4444 mL) was added TFA (0.44 mL, 5.98mmol). The mixture was stirred at 20° C. for 4 h. TLC (PE:EtOAc=1:1)showed a new spot (Rf=0) was detected. The mixture was concentrated toafford the title compound (55 mg, 0.2485 mmol, 99.851% yield) as yellowoil. The crude was used for next step directly.

[(1R,5S,6r)-6-(4-cyclopropyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone

To a solution of(1R,5S,6r)-6-(4-cyclopropyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (55 mg, 0.25 mmol), 1-isopropylimidazole-4-carboxylic acid(42.15 mg, 0.27 mmol) and DIPEA (0.14 mL, 0.87 mmol) in DMF (2.4444 mL)was added HATU (142.52 mg, 0.37 mmol). The mixture was stirred at 20° C.for 1 hr to give a brown mixture. LCMS showed the starting material wasconsumed and the desired peak was detected. The reaction mixture wasdiluted with H₂O (50 mL) and extracted by EtOAc (25 mL×3). The organicphase was washed with brine (50 mL×3), dried over anhydrous Na₂SO₄ andconcentrated to give a residue. The residue was purified by Prep-HPLC(NH₃) to afford the title compound (7.32 mg, 0.0205 mmol, 8.2398% yield)as white solid.

LC-MS Method1: 358.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (d, J=1.6 Hz, 1H), 7.47 (d, J=1.2Hz, 1H), 4.75 (d, J=12.0 Hz, 1H), 4.35 (spt, J=6.7 Hz, 1H), 4.16 (d,J=12.6 Hz, 1H), 3.96 (dd, J=4.3, 11.9 Hz, 1H), 3.64 (dd, J=4.4, 12.8 Hz,1H), 2.32-2.26 (m, 1H), 2.23 (td, J=3.8, 7.3 Hz, 1H), 2.03 (td, J=3.8,7.4 Hz, 1H), 1.50 (d, J=6.8 Hz, 6H), 1.46 (d, J=6.0 Hz, 6H), 1.43 (t,J=3.6 Hz, 1H), 0.75-0.68 (m, 4H)

Example 59(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanoneN-methyl-2-propanimine

To a solution of metylamine (1.3 mL, 32.2 mmol) and acetone (9349.65 mg,160.98 mmol) in DMF (22.976 mL) was added 4A MS (3000 mg, 32.2 mmol).The mixture was stirred at 110° C. for 4 h. The mixture was filtered togive the title compound (2000 mg, 2.8121 mmol, 8.7345% yield). The crudeproduct was used directly for next step.

tert-butyl(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of Et₃N (0.36 mL, 2.18 mmol) and N-methyl-2-propanimine(258.86 mg, 3.64 mmol) was added tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 0.73 mmol). The mixture was stirred at 20° C. for 16 hr. LCMSshowed desired mass. The mixture was diluted with H₂O (50 mL) andextracted by EtOAc (30 ml×2). The organic phase was washed with brine(50 mL), dried over anhydrous Na₂SO₄ and concentrated to give a residue.The residue was purified by flash column (PE:EtOAc=1:0-0:1) to affordthe title compound (140 mg, 0.4740 mmol, 65.109% yield) (PE:EtOAc=1:1,Rf=0.3) as a yellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.70 (d, J=11.2 Hz, 1H), 3.60 (d,J=11.2 Hz, 1H), 3.50-3.40 (m, 2H), 2.78 (s, 3H), 2.10-2.00 (m, 1H),2.00-1.90 (m, 1H), 1.44 (s, 9H), 1.41 (s, 6H). 1.16-1.14 (m, 1H).(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(140 mg, 0.47 mmol) in DCM (2.8 mL) was added TFA (0.56 mL, 7.54 mmol).The reaction mixture was stirred at 15° C. for 16 hr to give a brownmixture. LCMS showed the starting material was consumed up. The reactionmixture was concentrated to give the title compound as a brown oil. Theresidue was used for the next step directly.

LC-MS Method1 0.214 min, MS (m/z) 195.9 (M+H⁺).

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (72.64 mg,0.47 mmol) in DMF (3.5385 mL) were added HATU (135.48 mg, 0.71 mmol) andDIPEA (182.7 mg, 1.41 mmol). The reaction mixture was stirred at 15° C.for 30 min. Then(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (92 mg, 0.47 mmol) was added to the reaction. The reactionmixture was stirred at 15° C. for 0.5 hr to give a yellow mixture. LCMSshowed the desired MS. The reaction mixture was purified by prep-HPLC(NH₃) to give the title compound (18.72 mg, 0.0565 mmol, 11.989% yield)as white powder.

LC-MS Method1: 331.9 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.67 (d, J=1.2 Hz, 1H), 7.47 (d, J=1.2Hz, 1H), 4.75 (d, J=12.0 Hz, 1H), 4.35 (spt, J=6.7 Hz, 1H), 4.19 (d,J=12.4 Hz, 1H), 3.94 (dd, J=4.3, 12.0 Hz, 1H), 3.62 (dd, J=4.4, 12.8 Hz,1H), 2.76 (s, 3H), 2.20 (td, J=3.7, 7.3 Hz, 1H), 2.06-2.00 (m, 1H), 1.50(d, J=6.4 Hz, 6H), 1.40 (d, J=4.0 Hz, 6H), 1.15 (t, J=3.4 Hz, 1H)

Example 60[(1R,5S,6r)-6-(4-ethyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanonetert-butyl(1R,5S,6r)-6-(4-ethyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of Et₃N (0.36 mL, 2.18 mmol) and N-ethylpropan-2-imine(309.93 mg, 3.64 mmol) was added tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 0.73 mmol). The mixture was stirred at 20° C. for 16 hr. LCMSshowed the desired mass. The mixture was diluted with H₂O (50 mL) andextracted by EtOAc (30 mL×2). The organic phase was washed with brine(50 mL), dried over anhydrous Na₂SO₄ and concentrated to give a residue.The residue was purified by flash column (PE:EtOAc=1:0-0:1) to affordthe title compound (140 mg, 0.4525 mmol, 62.158% yield) (PE:EtOAc=1:1,Rf=0.3) as a yellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.68 (d, J=11.2 Hz, 1H), 3.58 (d,J=11.2 Hz, 1H), 3.45-3.30 (m, 2H), 3.18 (q, J=6.8 Hz, 2H), 2.30-2.20 (m,1H), 2.00-1.90 (m, 1H), 1.45 (s, 9H), 1.42 (s, 3H), 1.21 (t, J=6.8 Hz,3H), 1.14-1.13 (m, 1H).(1R,5S,6r)-6-(4-ethyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-(4-ethyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(140 mg, 0.45 mmol) in DCM (2.6731 mL) was added TFA (0.53 mL, 7.2mmol). The reaction mixture was stirred at 15° C. for 16 hr to give abrown mixture. LCMS showed the starting material was consumed up. Thereaction mixture was concentrated to give the title compound as brownoil. The residue was used for the next step directly.

LC-MS Method1 0.785 min, MS (m/z) 309.9 (M+H⁺).

[(1R,5S,6r)-6-(4-ethyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl(1-isopropyl-1H-imidazol-4-yl)methanone

To a solution of 1-isopropylimidazole-4-carboxylic acid (69.24 mg, 0.45mmol) in DMF (3.373 mL) were added HATU (129.15 mg, 0.67 mmol) and DIPEA(0.22 mL, 1.35 mmol). The reaction mixture was stirred at 15° C. for 30min. Then the(1R,5S,6r)-6-(4-ethyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (94 mg, 0.45 mmol) was added to the reaction. The reactionmixture was stirred at 15° C. for 0.5 hr to give a yellow mixture. LCMSshowed the desired MS. The reaction mixture was purified by prep-HPLC(NH₃) to give the title compound (9.9 mg, 0.0287 mmol, 6.3809% yield) asoff-white solid.

LC-MS Method1: 346.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) 5=7.67 (d, J=1.2 Hz, 1H), 7.47 (d, J=1.2Hz, 1H), 4.73 (d, J=12.0 Hz, 1H), 4.35 (m, 1H), 4.17 (d, J=12.6 Hz, 1H),3.96 (dd, J=4.0, 12.0 Hz, 1H), 3.64 (dd, J=4.0, 12.6 Hz, 1H), 3.16 (m,2H), 2.24 (m, 1H), 2.05 (m, 1H), 1.50 (d, J=6.8 Hz, 6H), 1.42 (d, J=5.6Hz, 6H), 1.19 (t, J=7.2 Hz, 3H), 1.14 (t, J=3.4 Hz, 1H)

Example 61(1-isopropyl-11H-imidazol-4-yl)[(1R,5S,6r)-6-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonetert-butyl(1R,5S,6r)-6-{[2-(2-pyridinyl)hydrazino]carbonyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (300 mg, 1.32 mmol) in DMF (5 mL) were added 2-hydrazinylpyridine(144.06 mg, 1.32 mmol), Et₃N (0.2 mL, 1.45 mmol), and HATU (555.13 mg,1.45 mmol). The reaction mixture was stirred at 15° C. for 16 h to givebrown mixture. The reaction mixture was concentrated in vacuo to give aresidue. The residue was purified by silica column (SiO₂, petroleumether: Ethyl acetate=6:1 to 0:1) to give the title compound (418 mg,1.3129 mmol, 99.459% yield) as yellow gum.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.55 (dd, J=4.4, 1.6 Hz, 1H), 8.27 (dd,J=9.2, 1.2 Hz, 1H), 8.03 (d, J=4.8 Hz, 1H), 7.57 (t, J=9.2 Hz, 1H), 7.29(dd, J=8.4, 4.4 Hz, 1H), 6.80-6.70 (m, 1H), 3.60-3.50 (m, 2H), 3.40-3.30(m, 3H), 2.10-2.00 (m, 2H), 1.47-1.46 (m, 1H), 1.35 (s, 9H).

tert-butyl(1R,5S,6r)-6-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of tert-butyl(1R,5S,6r)-6-{[2-(2-pyridinyl)hydrazino]carbonyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 0.63 mmol) in MeCN (4 mL) was added Burgess Reagent (149.7 mg,0.63 mmol). The reaction mixture was stirred at 90° C. for 12 h to giveyellow mixture. TLC (DCM/MeOH=10/1) showed the starting materials wasconsumed completely and a new spot was detected. The reaction mixturewas concentrated in vacuo to give residue. The residue was purified byprep-TLC (DCM/MeOH=10/1) to afford the title compound (64 mg, 0.2131mmol, 33.919% yield) as yellow solid.

LC-MS Method1 0.668, MS (m/z) 300.9 (M+H⁺).

3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl][1,2,4]triazolo[4,3-a]pyridineTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(66.2 mg, 0.22 mmol) in DCM (2 mL) was added TFA (0.2 mL, 2.61 mmol).The reaction mixture was stirred at 25° C. for 2 h to give yellowmixture. The reaction mixture was concentrated in vacuo to give thetitle compound. The crude product was used directly in the next step.

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl][1,2,4]triazolo[4,3-a]pyridineTFA salt (40 mg, 0.20 mmol) in DMF (2 mL) were added1-isopropylimidazole-4-carboxylic acid (30.8 mg, 0.20 mmol), Et₃N (0.11mL, 0.80 mmol), and HATU (114.55 mg, 0.30 mmol). The reaction mixturewas stirred at 25° C. for 12 h to give yellow mixture. The crude productwas purified by prep-HPLC (NH₃) to give the title compound (8.6 mg,12.8% yield) as yellow gum.

¹H NMR (400 MHz, CDCl₃) δ=7.97 (d, J=7.0 Hz, 1H), 7.68-7.62 (m, 2H),7.44 (s, 1H), 7.18-7.14 (m, 1H), 6.79 (t, J=6.8 Hz, 1H), 4.90 (d, J=12.0Hz, 1H), 4.40-4.19 (m, 2H), 4.00 (dd, J=4.1, 12.1 Hz, 1H), 3.69 (dd,J=4.1, 12.5 Hz, 1H), 2.50 (td, J=3.7, 7.3 Hz, 1H), 2.31 (td, J=3.7, 7.2Hz, 1H), 1.88 (t, J=3.3 Hz, 1H), 1.45 (d, J=6.8 Hz, 6H)

Example 62(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-([1,2,3]triazolo[1,5-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonetert-butyl(1R,5S,6r)-6-[hydroxy(2-pyridinyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.61 mL,1.42 mmol) in THF (6 mL) was added bromo(2-pyridyl)magnesium (3.2 mL,2.13 mmol) at 15° C. The reaction mixture was stirred at 0° C. for 4 hrto give a brown mixture. LCMS showed the desired MS. TLC (PE/EtOAc=1:2)showed a new spot.

The reaction mixture was quenched with H₂O (30 mL) and extracted withEtOAc (30 mL×2). The organic layer was washed with brine (30 mL×2),dried over anhydrous Na₂SO₄, filtrated and concentrated under reducedpressure to give a residue. The residue was purified by silica gelcolumn (PE/EtOAc=1:2) to give the title compound (200 mg, 0.6888 mmol,48.505% yield) as light yellow gum.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.53 (d, J=8.4 Hz, 1H), 7.75-7.65 (m,1H), 7.40-7.30 (m, 1H), 7.25-7.20 (m, 1H), 4.60-4.25 (m, 2H), 3.60-3.45(m, 2H), 3.40-3.30 (m, 2H), 1.80-1.60 (m, 2H), 1.43 (s, 9H), 1.00-0.90(m, 1H). tert-butyl(1R,5S,6r)-6-(2-pyridinylcarbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[hydroxy(2-pyridinyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 0.69 mmol) in DCM (4.1931 mL) was added DMP (292.15 mg, 0.69mmol) at 15° C. The reaction mixture was stirred at 15° C. for 20 min togive a white mixture. TLC (PE/EtOAc=1:1) showed a new spot. The reactionmixture was quenched with NaHCO₃ (30 mL) and extracted with DCM (30mL×2). The organic layer was washed with brine (30 mL×2), dried overanhydrous Na₂SO₄, filtrated and concentrated under reduced pressure togive a residue. The residue was purified by silica gel column(PE/EtOAc=1:1) to give the title compound (200 mg, 0.6936 mmol, 100.7%yield) as white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.77 (d, J=4.0 Hz, 1H), 8.10-7.90 (m,2H), 7.70 (dd, J=4.8, 3.6 Hz, 1H), 3.57 (d, J=11.2 Hz, 2H), 3.50-3.40(m, 2H), 3.24 (s, 1H), 2.23 (s, 2H), 1.41 (s, 3H). tert-butyl(1R,5S,6r)-6-([1,2,3]triazolo[1,5-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-(2-pyridinylcarbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.35 mmol) in EtOH (2.0973 mL) was added hydrazine hydrate(26.04 mg, 0.52 mmol). The reaction mixture was stirred at 60° C. for 6hr to give a colorless mixture. Then copper acetate (3.45 mg, 0.02mmol), ethyl acetate (10 mL) was added to the reaction mixture. Then thereaction mixture was stirred at 20° C. for 1 hr to give a colorlessmixture. LCMS showed the desired MS. The reaction mixture wasconcentrated to give a residue. The residue was purified by perp-TLC(PE/EtOAc=1:1) to give the title compound (20 mg, 0.0666 mmol, 19.2%yield) as colorless oil

LC-MS Method1 0.832 min, MS (m/z) 301.2 (M+H⁺).¹H NMR (400 MHz, CHLOROFORM-d) δ 8.65 (d, J=7.2 Hz, 1H), 7.69 (dd,J=7.6, 1.2 Hz, 1H), 7.19 (dd, J=8.0, 5.6 Hz, 1H), 6.95 (t, J=6.0 Hz,1H), 3.84 (d, J=11.2 Hz, 1H), 3.75 (d, J=11.2 Hz, 1H), 3.60-3.50 (m,2H), 2.35-2.25 (m, 1H), 2.20-2.10 (m, 1H), 1.95-1.90 (m, 1H), 1.48 (s,9H).

3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl][1,2,3]triazolo[1,5-a]pyridineTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-([1,2,3]triazolo[1,5-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(30 mg, 0.10 mmol) in DCM (3.14 mL) was added TFA (0.01 mL, 0.10 mmol).The reaction mixture was stirred at 20° C. for 16 hr to give a colorlessmixture. TLC (PE/EtOAc=1:1) showed a new spot. The reaction mixture wasremoved the solvent to give the title compound. The residue was used forthe next step directly.

LC-MS Method1 0.289 min, MS (m/z) 200.9 (M+H⁺).

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-([1,2,3]triazolo[1,5-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 1-isopropylimidazole-4-carboxylic acid (23.1 mg, 0.15mmol) in DMF (1.1251 mL) were added HATU (43.08 mg, 0.22 mmol) and DIPEA(0.07 mL, 0.45 mmol). The reaction mixture was stirred at 15° C. for 30min. Then3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl][1,2,3]triazolo[1,5-a]pyridineTFA salt (30 mg, 0.15 mmol) was added to the reaction. The reactionmixture was stirred at 15° C. for 0.5 hr to give a yellow mixture. LCMSshowed the desired MS. The reaction mixture was purified by prep-HPLC(FA) to give the title compound (14.4 mg, 0.0428 mmol, 28.573% yield) aswhite powder.

LC-MS Method1: 337.1 [M+H⁺]

¹H NMR (400 MHz, DMSO-d₆) δ=8.94 (d, J=7.2 Hz, 1H), 8.12-7.73 (m, 3H),7.35-7.22 (m, 1H), 7.10 (m, 1H), 4.77-4.41 (m, 2H), 4.22-3.85 (m, 2H),3.60 (br s, 1H), 2.35-2.24 (m, 1H), 2.20-2.08 (m, 2H), 1.44 (br d, J=5.6Hz, 6H)

Example 63(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonetert-butyl(1R,5S,6r)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

A solution of(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (1000 mg, 4.4 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (713.47 mg,5.28 mmol), N-ethyl-N-isopropylpropan-2-amine (0.91 mL, 5.28 mmol) andEDCI (1012.23 mg, 5.28 mmol) in DCM (10 mL) was stirred at 10° C. for 30min. Then it was cooled to 0° C. and NH₃/EtOH (5 mL, 40 mmol) was addeddrop-wise to stirred for 16 hr to give a white suspension. TLC(DCM/MeOH=10/1 Rf=0.1) showed a new spot was detected. H₂O (10 mL) wasadded and it was extracted with EtOAc (10 mL×2). The combined organiclayer dried over Na₂SO₄ and concentrated in vacuum to give the titlecompound (1050 mg, 4.6405 mmol, 105.46% yield) as white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=5.59 (brs, 1H), 5.29 (brs, 1H), 3.61(d, J=11.2 Hz, 1H), 3.59 (d, J=11.2 Hz, 1H), 3.45-3.35 (m, 2H), 2.27 (t,J=7.2 Hz, 1H), 2.01 (brs, 2H), 1.37 (s, 9H).

tert-butyl (1R,5S,6r)-6-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (620 mg,2.74 mmol) in DMF (12.4 mL) was added 2,4,6-trichloro-1,3,5-triazine(0.57 mL, 5.48 mmol). The reaction mixture was stirred at 15° C. for 16hr to give a yellow solution. TLC (PE/EA=3/1 Rf=0.2) showed a new spotwas detected. H₂O (30 mL) was added and it was extracted with EtOAc (30mL×2). The combined organic layer dried over Na₂SO₄ and concentrated invacuum to give the title compound as a yellow oil. The crude waspurified by silica gel chromatography (PE/EA=10/1 to 3/1) to give thetitle compound (380 mg, 1.8246 mmol, 66.591% yield) as colorless oil.

tert-butyl(1R,5S,6r)-6-(1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A mixture of tert-butyl(1R,5S,6r)-6-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate (330 mg, 1.58mmol), ammonia hydrochloride (169.52 mg, 3.17 mmol) and NaN₃ (206.02 mg,3.17 mmol) in DMF (7.3333 mL) was stirred at 120° C. for 24 hr to give ayellow solution. TLC (EA, Rf=0.1) showed a new spot was detected. H₂O(10 mL) was added and it was extracted with EtOAc (15 mL×3). Thecombined organic layer was dried over Na₂SO₄ and concentrated in vacuumto give the title compound (380 mg, 1.5123 mmol, 95.437% yield) asyellow oil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.95 (brs, 1H), 3.70-3.40 (m, 4H), 2.15(brs, 2H), 1.96 (t, J=3.2 Hz, 1H), 1.40 (s, 9H).

(1R,5S,6r)-6-(1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexane TFA salt

tert-butyl(1R,5S,6r)-6-(1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(120 mg, 0.4800 mmol) was dissolved in HCl/dioxane (2 mL, 0.4800 mmol)and it was stirred at 15° C. for 2 hr to give a colorless solution. Thereaction was evaporated in vacuum to give the title compound as acolorless oil. It was directly used in the next step.

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

A 100 mL round-bottom flask was charged with1-isopropylimidazole-4-carboxylic acid (60 mg, 0.39 mmol), HATU (163.66mg, 0.43 mmol), N-ethyl-N-isopropylpropan-2-amine (0.27 mL, 1.56 mmol)and DMF (3 mL). After stirred for 30 min,(1R,5S,6r)-6-(1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexane TFA salt(103.21 mg, 0.39 mmol) was added. The reaction mixture was stirred at20° C. for 16 hr to give a yellow solution. H₂O (10 mL) was added and itwas extracted with EtOAc (10 mL×2). The H₂O layer was purified byPrep-HPLC (NH₃). The afforded flows were concentrated in vacuum toremove most of CH₃CN and lyophilized to give the title compound (37.35mg, 0.13 mmol, 33.402% yield) as white solid.

LC-MS Method1: 288.0 [M+H⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (br s, 1H), 8.32 (s, 1H), 4.65 (td,J=6.64, 13.35 Hz, 1H), 4.17 (br d, J=10.88 Hz, 1H), 3.98-4.08 (m, 2H),2.42 (br d, J=3.25 Hz, 1H), 2.32 (br d, J=3.75 Hz, 1H), 2.13 (t, J=3.31Hz, 1H), 1.50 (d, J=6.63 Hz, 6H)

Example 64(1R,5S,6r)-N-(propan-2-yl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamidetert-butyl(1R,5S,6r)-6-(isopropylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (100 mg, 0.44 mmol) in DMF (1.5 mL) were added HATU (201.87 mg,0.5300 mmol), Et₃N (0.22 mL, 1.32 mmol) and propan-2-amine (52.02 mg,0.8800 mmol). The mixture was stirred at 20° C. for 12 h to give yellowsolution. TLC (PE:EtOAc 1:1) showed a new spot (Rf=0, 0.7). The reactionmixture was poured into H₂O (10 mL) and extracted with EtOAc (10 mL×4).The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to afford thetitle compound (110 mg 0.4099 mmol, 93.157% yield) (crude) as a whitesolid.

(1R,5S,6r)-N-isopropyl-3-azabicyclo[3.1.0]hexane-6-carboxamide TFA salt

To a solution of(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (110 mg, 0.4100 mmol) in DCM (2.8947 mL) was added TFA (0.58 mL,7.79 mmol). The resulting mixture was stirred at 20 to 25° C. for 30 minto give yellow solution. TLC (PE:EtOAc=1:1) showed a new spot (Rf=0,0.4). The reaction mixture was filtered and concentrated under reducedpressure to afford the title compound (110 mg, 0.3897 mmol, 95.072%yield) (crude) as yellow oil.

(1R,5S,6r)-N-(propan-2-yl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a solution of 1-isopropylimidazole-4-carboxylic acid (120.16 mg, 0.78mmol) in DMF (2 mL) were added HATU (193.68 mg, 0.51 mmol), Et₃N (0.19mL, 1.17 mmol) and(1R,5S,6r)-N-isopropyl-3-azabicyclo[3.1.0]hexane-6-carboxamide TFA salt(110 mg, 0.39 mmol). The resulting mixture was stirred at 20 to 25° C.for 12 hours to give yellow solution. The reaction mixture was pouredinto H₂O (10 mL) and extracted with EtOAc (10 mL×4). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by prep-HPLC (NH₃). Theafforded flows were combined and concentrated to remove most of CH₃CNand lyophilized to afford the title compound (50.32 mg, 0.1653 mmol,42.42% yield) as white solid.

LC-MS Method1: 305.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.65 (d, J=1.3 Hz, 1H), 7.47 (d, J=1.3Hz, 1H), 5.41 (br d, J=7.8 Hz, 1H), 4.74 (d, J=11.8 Hz, 1H), 4.35 (spt,J=6.7 Hz, 1H), 4.17-4.02 (m, 2H), 3.90 (dd, J=4.0, 12.0 Hz, 1H), 3.61(dd, J=4.0, 12.5 Hz, 1H), 2.19 (td, J=3.7, 7.2 Hz, 1H), 2.10 (td, J=3.4,7.3 Hz, 1H), 1.50 (d, J=6.8 Hz, 6H), 1.16-1.13 (m, 6H)

Example 65(1R,5S,6r)-N-tert-butyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamidetert-butyl (1R,5S,6r)-6-[(tert-butylcarbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (200 mg, 0.88 mmol) in Pyridine (2 mL) was added2-methylpropan-2-amine (0.11 mL, 1.06 mmol). The reaction mixture wasstirred at 20° C. for 0.5 hr to give a mixture. Then the EDCI (337.41mg, 1.76 mmol) was added to the reaction mixture. The reaction mixturewas stirred at 20° C. for 2 hr to give a brown mixture. TLC(PE/EtOAc=1:1) showed a new spot. The reaction mixture was diluted withH₂O (10 mL) and extracted with EtOAc (20 mL×2). The organic layer wasdried over anhydrous Na₂SO₄, filtrated and concentrated under reducedpressure to give a residue. The residue was purified by prep-TLC(PE/EtOAc=1:1) to give the title compound (200 mg, 0.7083 mmol, 80.48%yield) as white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=5.43 (brs, 1H), 3.64 (d, J=11.2 Hz,1H), 3.55 (d, J=11.2 Hz, 1H), 3.45-3.35 (m, 2H), 1.99 (s, 2H), 1.43 (s,9H), 1.34 (s, 9H), 1.10-1.05 (m, 1H).

(1R,5S,6r)-N-(tert-butyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide THAsalt

To a solution of tert-butyl(1R,5S,6r)-6-[(tert-butyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.35 mmol) in DCM (1.3333 mL) was added TFA (0.01 mL, 0.07mmol). The reaction mixture was stirred at 20° C. for 16 hr to give acolorless mixture. LCMS showed the desired MS. The reaction mixture wasremoved the solvent to give the title compound. The compound was usedfor the next step directly.

LC-MS Method1 0.293 min, MS (m/z) 182.9 (M+H⁺).

(1R,5S,6r)-N-tert-butyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a solution of 1-isopropylimidazole-4-carboxylic acid (54.14 mg, 0.35mmol) in Pyridine (2.6371 mL) was added EDCI (134.63 mg, 0.70 mmol). Thereaction mixture was stirred at 15° C. for 30 min. Then(1R,5S,6r)-N-(tert-butyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide THAsalt (64 mg, 0.35 mmol) was added to the reaction. The reaction mixturewas stirred at 15° C. for 0.5 hr to give a yellow mixture. The reactionmixture was quenched with H₂O and the resulting residue was purified byprep-HPLC (NH₃) to give the title compound (37.57 mg, 0.1180 mmol,33.602% yield) as light yellow solid.

LC-MS Method1: 319.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.63 (d, J=1.2 Hz, 1H), 7.46 (d, J=1.2Hz, 1H), 5.44 (s, 1H), 4.72 (d, J=11.2 Hz, 1H), 4.34 (spt, J=6.7 Hz,1H), 4.11 (d, J=12.4 Hz, 1H), 3.87 (dd, J=3.6, 11.8 Hz, 1H), 3.58 (dd,J=4.4, 12.8 Hz, 1H), 2.16-2.09 (m, 1H), 2.04 (td, J=3.5, 7.3 Hz, 1H),1.49 (d, J=6.8 Hz, 6H), 1.33 (s, 9H), 1.10 (t, J=3.1 Hz, 1H)

Example 66(1R,5S,6r)-N-tert-butyl-N-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamidetert-butyl(1R,5S,6r)-6-[methyl(tert-butyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(tert-butyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(50 mg, 0.18 mmol) in DMF (2.4909 mL) was added NaH (8.5 mg, 0.35 mmol)at 20° C. Then the reaction mixture was stirred at 20° C. for 1 hr. ThenMeI (0.04 mL, 0.71 mmol) in DMF (2.4909 mL) was added. The reactionmixture was stirred at 50° C. for 2 hr to give a light yellow mixture.TLC (PE/EtOAc=1:1) showed the new spot. The reaction mixture wasquenched with H₂O (10 mL) and extracted with EtOAc (10 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtrated and concentrated underreduced pressure to give the title compound (52 mg, 0.1754 mmol, 99.077%yield) as brown oil

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.66 (d, J=11.2 Hz, 1H), 3.60 (d,J=11.2 Hz, 1H), 3.50-3.40 (m, 2H), 3.02 (s, 3H), 2.10-2.00 (m, 1H),2.00-1.90 (m, 1H), 1.50-1.40 (m, 1H), 1.44 (s, 9H), 1.38 (s, 9H),(1R,5S,6r)-N-methyl-N-(tert-butyl)-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-[methyl(tert-butyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(52 mg, 0.18 mmol) in DCM (1 mL) was added TFA (0.1 mL, 1.35 mmol). Thereaction mixture was stirred at 20° C. for 16 hr to give a brownmixture. TLC (PE/EtOAc=1:1) showed a new spot. The reaction mixture wasconcentrated under reduced pressure to give the title compound and itwas used for the next step directly.

(1R,5S,6r)-N-tert-butyl-N-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a solution of 1-isopropylimidazole-4-carboxylic acid (78.54 mg, 0.51mmol) in Pyridine (3.826 mL) was added EDCI (195.32 mg, 1.02 mmol). Thereaction mixture was stirred at 15° C. for 30 min. Then(1R,5S,6r)-N-methyl-N-(tert-butyl)-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt (100 mg, 0.51 mmol) was added to the reaction. The reactionmixture was stirred at 15° C. for 0.5 hr to give a yellow mixture. LCMSshowed the desired MS. The reaction mixture was purified by prep-HPLC(NH₃) to give the title compound (16.42 mg, 0.0494 mmol, 9.6952% yield)as light yellow solid.

LC-MS Method1: 333.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.66 (d, J=1.2 Hz, 1H), 7.47 (d, J=1.2Hz, 1H), 4.66 (d, J=12.0 Hz, 1H), 4.40-4.31 (m, 1H), 4.11 (d, J=12.8 Hz,1H), 3.97 (dd, J=4.3, 12.0 Hz, 1H), 3.65 (dd, J=4.3, 12.8 Hz, 1H), 3.00(s, 3H), 2.20 (td, J=3.8, 7.5 Hz, 1H), 2.05 (td, J=3.8, 7.4 Hz, 1H),1.50 (d, J=6.8 Hz, 6H), 1.38 (s, 9H)

Example 67(1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamidetert-butyl(1R,5S,6r)-6-[(1-methylcyclopropyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (500 mg, 2.2 mmol) in DCM (20 mL) were added Et₃N (0.73 mL, 4.4mmol) and HATU (1.26 g, 3.3 mmol). After 10 min,1-methylcyclopropanamine hydrochloride (236.69 mg, 2.2 mmol) was added.The resulting mixture was stirred at 20° C. for 6 hours to give brownmixture. LCMS showed the desired peak was found. The reaction wasdiluted with H₂O (20 mL) and extracted with EtOAc (30 ml×3). Thecombined organic layers were separated, then dried over Na₂SO₄ andconcentrated in vacuum to give brown oil. The crude oil was purified byprep-TLC (PE/EtOAc=1/1) to give the title compound (590 mg, 2.1044 mmol,95.651% yield) as white solid.

LC-MS Method1: 227.0 [M+H⁺]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=6.15-5.95(m, 1H), 3.70-3.59 (m, 1H), 3.58-3.48 (m, 1H), 3.45-3.25 (m, 2H),2.07-1.96 (m, 2H), 1.46-1.40 (m, 9H), 1.36 (s, 3H), 1.13-1.04 (m, 1H),0.78-0.70 (m, 2H), 0.65-0.57 (m, 2H) tert-butyl(1R,5S,6r)-6-[methyl(1-methylcyclopropyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of tert-butyl(1R,5S,6r)-6-[(1-methylcyclopropyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.4000 mmol) in THF (5 mL) was added NaH (23.78 mg, 0.5900mmol). The reaction mixture was then stirred at 0° C. for 15 min. ThenMeI (0.03 mL, 0.4800 mmol) was added. The reaction mixture was stirredat 15° C. for 16 hr. TLC (PE/EA=1/1) showed a new spot (Rf=0.5) and thereaction was completed. The mixture was diluted with H₂O (20 mL),extracted with EA (10 mL×2), and then washed with H₂O (10 mL) and NH₄Cl(10 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuum to give crude oil. The crude oil was purified byprep-TLC (PE/EA=1/1) to give the title compound (100 mg, 0.3755 mmol,94.732% yield) as off-white solid.

LC-MS Method1 0.825 min, MS (m/z) 295 (M+H⁺).

(1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-[methyl(1-methylcyclopropyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.34 mmol) in DCM (2 mL) was added TFA (0.15 mL, 2.04 mmol) at20° C. The mixture was stirred at 20° C. for 2 hours. LCMS showed thedesired peak was found. The reaction mixture was concentrated underreduced pressure to give the title compound (100 mg, crude product) asyellow oil.

LC-MS Method1: 195.0 [M+H⁺].(1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a mixture of 1-isopropylimidazole-4-carboxylic acid (75 mg, 0.49mmol) in DCM (5 mL) were added HATU (278.97 mg, 0.73 mmol) and Et₃N(0.16 mL, 0.97 mmol). The mixture was stirred at 20° C. for 10 min underN₂. Then(1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt (94.51 mg, 0.49 mmol) in DCM (3 mL) was added. The resultingmixture was stirred at 20° C. for 16 hr to give brown mixture. LCMSshowed the desired peak was found. The reaction was diluted with H₂O (20mL) and extracted with DCM (20 mL). The combined organic layers wereseparated, then dried over Na₂SO₄ and concentrated in vacuum to givebrown oil. The brown oil was purified by prep-HPLC (FA). The affordedflows were combined, concentrated to remove most of CH₃CN, added NH₃H₂O(0.5 mL) and lyophilized to afford the title compound (20 mg, 0.0605mmol, 12.442% yield) as yellow solid.

LC-MS Method1: 331.1 [M+H⁺].

¹H NMR (400 MHz, DMSO-d₆) δ=7.80 (br s, 2H), 4.66-4.37 (m, 2H),4.00-3.78 (m, 2H), 3.50 (br d, J=5.1 Hz, 1H), 2.77 (s, 3H), 2.13-1.92(m, 2H), 1.91-1.83 (m, 1H), 1.40 (d, J=6.6 Hz, 6H), 1.28 (s, 3H),1.09-0.54 (m, 4H)

Example 68(1R,5S,6r)-N-(1-cyanocyclopropyl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamideethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate TFA salt

To a mixture of 6-ethyl 3-(tert-butyl)(1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (600 mg, 2.35mmol) in DCM (10 mL) was added TFA (1 mL, 13.46 mmol). The reaction wasstirred at 25° C. for 3 h to give brown mixture. The reaction mixturewas concentrated in vacuo to give the title compound (300 mg, crude).

ethyl(1R,5S,6r)-3-[(1-isopropyl-1H-imidazol-4-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylate

To a solution of ethyl(1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate TFA salt (300 mg,1.18 mmol) in THF (4 mL) were added Et₃N (0.81 mL, 5.88 mmol),1-isopropylimidazole-4-carboxylic acid (181.16 mg, 1.18 mmol) and HATU(583.98 mg, 1.53 mmol). The resulting mixture was stirred at 20° C. for12 h to give yellow mixture. The reaction mixture was concentrated andpurified by silica column to give the title compound (170 mg, crude) aslight yellow gum.

LC-MS Method1 0.598 min, MS (m/z) 291.9 (M+H⁺).

(1R,5S,6r)-3-[(1-isopropyl-1H-imidazol-4-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylicacid

To a mixture of ethyl(1R,5S,6r)-3-[(1-isopropyl-1H-imidazol-4-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylate(170 mg, 0.58 mmol) in THF/H₂O (4 mL, 3/1) was added hydroxylithiumhydrate (31.83 mg, 0.76 mmol). The reaction was stirred at 25° C. for 12h to give yellow mixture. TLC showed the starting material was consumedup. The reaction mixture was concentrated in vacuo to give the titlecompound (153 mg, crude) as light yellow solid.

LC-MS Method1 0.218 min, MS (m/z) 263.9 (M+H⁺).

(1R,5S,6r)-N-(1-cyanocyclopropyl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a solution(1R,5S,6r)-3-[(1-isopropyl-1H-imidazol-4-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (153 mg, 0.58 mmol) in DMF (2 mL) were added HATU (244.37 mg, 0.64mmol), Et₃N (0.3 mL, 2.32 mmol) and 1-aminocyclopropanecarbonitrilehydrochloride (82.68 mg, 0.70 mmol). The reaction mixture was stirred at25° C. for 12 h to give yellow mixture. The reaction mixture wasconcentrated in vacuo to give residue. The crude product was purified byprep-HPLC (NH₃) to give the title compound (5.98 mg) as a white solid

LC-MS Method1: 328.1 [M+H⁺]

¹H NMR (400 MHz, CDCl₃) δ=7.56 (d, J=1.0 Hz, 1H), 7.40 (d, J=1.1 Hz,1H), 6.69 (s, 1H), 4.63 (d, J=12.1 Hz, 1H), 4.37-4.23 (m, 1H), 4.02 (d,J=12.5 Hz, 1H), 3.81 (dd, J=3.9, 11.9 Hz, 1H), 3.52 (dd, J=4.1, 12.6 Hz,1H), 2.22-2.15 (m, 1H), 2.11-2.03 (m, 1H), 1.46 (br d, J=2.5 Hz, 2H),1.43 (d, J=6.8 Hz, 6H), 1.18 (br d, J=4.1 Hz, 2H), 1.13 (t, J=3.1 Hz,1H)

Example 69(1R,5S,6r)-N-(1-cyanocyclopropyl)-N-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide(1R,5S,6r)-N-(1-cyanocyclopropyl)-N-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a mixture of(1R,5S,6r)-N-(1-cyanocyclopropyl)-3-[(1-isopropyl-1H-imidazol-4-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide(15 mg, 0.05 mmol) in DMF (0.50 mL)/THF (0.50 ml) was added NaH (2.75mg, 0.07 mmol) under ice-cooling. The reaction mixture was stirred for0.3 h. Then MeI (19.51 mg, 0.14 mmol) was added. The mixture was stirredat 30° C. for 3 h. The reaction mixture was concentrated directly. Thenthe residue was purified by prep-HPLC (NH₃) to afford the title compound(2.8 mg, 0.0176 mmol, 38.356% yield) as white solid.

LC-MS Method1: 341.9 [M+H⁺] ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.63 (br s,1H), 7.41 (s, 1H), 4.64 (br s, 1H), 4.34-4.22 (m, 1H), 4.11-3.92 (m,2H), 3.66 (br s, 1H), 3.00-2.85 (m, 3H), 2.28 (br s, 1H), 2.12 (br s,1H), 1.84 (br s, 1H), 1.44 (d, J=6.8 Hz, 7H), 1.18 (s, 4H) Example 70(1R,5S,6r)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-N-[1-(trifluoromethyl)cyclopropyl]-3-azabicyclo[3.1.0]hexane-6-carboxamidetert-butyl(1R,5S,6r)-6-{[1-(trifluoromethyl)cyclopropyl]carbamoyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (200 mg, 0.88 mmol) in DMF (3 mL) were added HATU (370.09 mg, 0.97mmol), Et₃N (0.34 mL, 2.64 mmol) and 1-(trifluoromethyl)cyclopropanaminehydrochloride (170.61 mg, 1.06 mmol). The resulting mixture was stirredat 25° C. for 12 h. TLC (PE:EtOAc=1:1) showed the reaction wascompleted. The reaction mixture was poured into H₂O (10 ml) andextracted with EtOAc (10 ml×3). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash column (PE to 40% EtOAc in PE) to affordthe title compound (328 mg, 0.9811 mmol, 111.48% yield, crude product)as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=6.47 (s, 1H), 3.68-3.53 (m, 2H), 3.41(br d, J=11.3 Hz, 2H), 2.12-2.03 (m, 2H), 1.48-1.46 (m, 1H), 1.44 (s,9H), 1.31 (br s, 2H), 1.19 (t, J=3.1 Hz, 1H), 1.10 (br d, J=5.5 Hz, 2H)(1R,5S,6r)-N-[1-(trifluoromethyl)cyclopropyl]-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-{[1-(trifluoromethyl)cyclopropyl]carbamoyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate(50 mg, 0.15 mmol) in DCM (2 mL) was added 2,2,2-trifluoroacetic acid(0.3 mL, 3.92 mmol). The resulting mixture was stirred at 20 to 25° C.for 2 h. TLC (PE:EtOAc=1:1) showed the reaction was completed. Themixture was concentrated by purging with N₂ to afford the title compound(30 mg, 0.1281 mmol, 85.645% yield) as a white solid.

(1R,5S,6r)-3-[1-(propan-2-yl]-1H-imidazole-4-carbonyl]-N-[1-(trifluoromethyl)cyclopropyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a solution of 1-isopropylimidazole-4-carboxylic acid (19.75 mg, 0.13mmol) in DMF (2 mL) were added Et₃N (0.08 mL, 0.64 mmol), HATU (58.76mg, 0.15 mmol) and(1R,5S,6r)-N-[1-(trifluoromethyl)cyclopropyl]-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt (30 mg, 0.13 mmol). The resulting mixture was stirred at 20 to25° C. for 16 h. The mixture was filtered and the filtrate was purifiedby prep-HPLC (NH₃). The afforded flows were combined, concentrated toremove most of CH₃CN and lyophilized to afford the title compound (3.97mg, 0.0107 mmol, 8.3687% yield) as a white solid.

LC-MS Method1: 371.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.67 (s, 1H), 7.49 (s, 1H), 6.13 (br s,1H), 4.77 (br d, J=12.0 Hz, 1H), 4.43-4.31 (m, 1H), 4.16 (br d, J=12.8Hz, 1H), 3.90 (dd, J=3.9, 12.3 Hz, 1H), 3.62 (dd, J=3.5, 13.3 Hz, 1H),2.23 (br d, J=3.8 Hz, 1H), 2.15 (br d, J=3.3 Hz, 1H), 1.52 (d, J=6.6 Hz,7H), 1.37-1.32 (m, 2H), 1.27 (s, 2H), 1.21 (br s, 2H), 1.13 (br d, J=7.6Hz, 2H)

Example 71(1R,5S,6r)-N-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-N-[1-(trifluoromethyl)cyclopropyl]-3-azabicyclo[3.1.0]hexane-6-carboxamidetert-butyl(1R,5S,6r)-6-{methyl[1-(trifluoromethyl)cyclopropyl]carbamoyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of tert-butyl(1R,5S,6r)-6-{[1-(trifluoromethyl)cyclopropyl]carbamoyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate(180 mg, 0.54 mmol) in DMF (2.52 mL) was added NaH (19.38 mg, 0.81 mmol)under ice-cooling after stirring for 0.5 h. Then MeI (382.1 mg, 2.69mmol) was added. The mixture was stirred at 30° C. for 3 h. TLC(PE:EtOAc=5:1) showed the reaction was completed (Rf=0.2). The reactionmixture was poured into H₂O (10 mL) and extracted with EtOAc (10 mL×4).The combined organic layers were washed with sat. aq. (10 mL×4), driedover Na₂SO₄, filtered and concentrated under reduced pressure to affordthe title compound (180 mg, 0.5167 mmol, 95.973% yield) as a yellow oil.

(1R,5S,6r)-N-methyl-N-[1-(trifluoromethyl)cyclopropyl]-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-{methyl[1-(trifluoromethyl)cyclopropyl]carbamoyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate(220 mg, 0.63 mmol) in DCM (3 mL) was added 2,2,2-trifluoroacetic acid(0.3 mL, 3.92 mmol). The resulting mixture was stirred at 20 to 25° C.for 2 h. TLC (PE:EtOAc=5:1) showed the reaction was completed. Themixture was concentrated by purging with N₂ to afford the title compound(150 mg, 0.6043 mmol, 95.681% yield) as a brown solid.

(1R,5S,6r)-N-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-N-[1-(trifluoromethyl)cyclopropyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a solution of 1-isopropylimidazole-4-carboxylic acid (93.16 mg, 0.60mmol) in DMF (2 mL) were added HATU (277.21 mg, 0.73 mmol) and Et₃N(0.39 mL, 3.02 mmol). The mixture was stirred at 20 to 25° C. for 0.5 h.(1R,5S,6r)-N-methyl-N-[1-(trifluoromethyl)cyclopropyl]-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt (150 mg, 0.60 mmol) was added and the reaction mixture wasstirred at 20-25° C. for 16 h. The mixture was then filtered and thefiltrate was concentrated. The residue was purified by prep-HPLC (NH₃).The afforded flows were combined, concentrated to remove most of CH₃CNand lyophilized to afford the title compound (36.84 mg, 0.0958 mmol,15.86% yield) as a yellow solid.

LC-MS Method1: 385.0 [M+H⁺]

¹H NMR (400 MHz, DMSO-d₆) δ=7.79 (br d, J=8.3 Hz, 2H), 4.59-4.39 (m,2H), 3.94-3.74 (m, 2H), 3.52 (br d, J=12.0 Hz, 1H), 3.15 (s, 1H), 2.89(s, 3H), 2.17 (br s, 1H), 2.06 (br s, 1H), 1.95 (br s, 1H), 1.80 (br s,1H), 1.72-1.51 (m, 2H), 1.40 (d, J=6.8 Hz, 7H)

Example 72(1R,5S,6r)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamidetert-butyl(1R,5S,6r)-6-[(1,1,1-trifluoro-2-methylpropan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (100 mg, 0.44 mmol) and HATU (126.53 mg, 0.66 mmol) in DMF (3.3046mL) was added DIPEA (0.22 mL, 1.32 mmol). The reaction mixture wasstirred at 15° C. for 30 min. Then1,1,1-trifluoro-2-methyl-propan-2-amine (55.93 mg, 0.44 mmol) was added.The reaction mixture was stirred at 15° C. for 0.5 hr to give a yellowmixture. LCMS showed the desired MS. TLC (PE/EtOAc=1:1) showed a newspot. The reaction mixture was diluted with H₂O (50 mL) and extractedwith EtOAc (30 mL×2). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated to give a residue. The residue waspurified by silica column (PE/EtOAc=1:1) to give the title compound (90mg, 0.2676 mmol, 60.81% yield) as white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=5.75 (s, 1H), 3.65 (d, J=11.2 Hz, 1H),3.57 (d, J=11.2 Hz, 1H), 3.45-3.35 (m, 2H), 2.02 (brs, 2H), 1.59 (s,6H), 1.45 (s, 9H).

(1R,5S,6r)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-[(1,1,1-trifluoro-2-methylpropan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(90 mg, 0.27 mmol) in DCM (2 mL) was added TFA (9.53 mg, 0.27 mmol). Thereaction mixture was stirred at 25° C. for 0.5 hr to give a colorlessmixture. TLC (PE/EtOAc=1:1) showed a new spot. The solvent was removedby evaporation to afford the title compound as yellow oil.

(1R,5S,6r)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a solution of 1-isopropylimidazole-4-carboxylic acid (41.12 mg, 0.27mmol) and HATU (76.69 mg, 0.40 mmol) in DMF (2.0028 mL) was added DIPEA(0.13 mL, 0.80 mmol). The reaction mixture was stirred at 15° C. for 30min. Then(1R,5S,6r)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt (63 mg, 0.27 mmol) was added to the reaction. The reactionmixture was stirred at 15° C. for 0.5 hr to give a yellow mixture. LCMSshowed the desired MS. The reaction mixture was purified by prep-HPLC(NH₃) to give the title compound (37.38 mg, 0.1004 mmol, 37.639% yield)as light yellow solid.

LC-MS Method1: 373.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.64 (d, J=1.2 Hz, 1H), 7.46 (d, J=1.2Hz, 1H), 5.70 (s, 1H), 4.74 (d, J=12.0 Hz, 1H), 4.35 (m, 1H), 4.14 (d,J=12.3 Hz, 1H), 3.87 (dd, J=3.9, 11.9 Hz, 1H), 3.58 (dd, J=3.9, 12.4 Hz,1H), 2.19-2.01 (m, 2H), 1.57 (d, J=5.5 Hz, 6H), 1.49 (d, J=6.8 Hz, 6H),1.20 (t, J=3.0 Hz, 1H)

Example 73(1R,5S,6r)-N-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamidetert-butyl(1R,5S,6r)-6-[methyl(1,1,1-trifluoro-2-methylpropan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(1,1,1-trifluoro-2-methylpropan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(160 mg, 0.48 mmol) in THF (7.4294 mL) was added NaH (13.7 mg, 0.57mmol) at 0° C. and the mixture was stirred at 0° C. for 0.5 hr to give ayellow mixture. MeI (0.04 mL, 0.67 mmol) was added to the reactionmixture. The reaction mixture was stirred at 20° C. for 16 hr to give alight yellow mixture. TLC (PE/EtOAc=1:1) showed a new spot. LCMS showedthe desired MS. The reaction mixture was quenched with H₂O (100 mL) andextracted with EtOAc (50 mL×3). The organic layer was concentrated togive a residue. The residue was purified by silica column (PE/EtOAc=1:1)to give the title compound (150 mg, 0.4281 mmol, 89.996% yield) ascolorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.66 (d, J=11.2 Hz, 1H), 3.55 (d,J=11.2 Hz, 1H), 3.50-3.40 (m, 2H), 3.15 (s, 3H), 2.20-2.10 (m, 1H),2.10-2.00 (m, 1H), 1.66 (s, 6H), 1.60-1.50 (m, 1H), 1.44 (s, 9H).

(1R,5S,6r)-N-methyl-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-[methyl(1,1,1-trifluoro-2-methylpropan-2-yl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.29 mmol) in DCM (2.1332 mL) was added TFA (10.16 mg, 0.29mmol). The reaction mixture was stirred at 25° C. for 0.5 hr to give acolorless mixture. TLC (PE/EtOAc=1:1) showed a new spot. The reactionmixture was removed the solvent to give the title compound. It was usedfor the next step directly.

(1R,5S,6r)-N-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a solution of 1-isopropylimidazole-4-carboxylic acid (43.74 mg, 0.28mmol), HATU (81.58 mg, 0.43 mmol) in DMF (2.1306 mL) was added DIPEA(0.14 mL, 0.85 mmol). The reaction mixture was stirred at 15° C. for 30min. Then(1R,5S,6r)-N-methyl-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt (71 mg, 0.28 mmol) was added to the reaction. The reactionmixture was stirred at 15° C. for 0.5 hr to give a yellow mixture. LCMSshowed the desired MS. The reaction mixture was purified by prep-HPLC(NH₃) to give the title compound (72.14 mg, 0.1867 mmol, 65.805% yield)as white powder.

LC-MS Method1: 387.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.67 (d, J=1.6 Hz, 1H), 7.47 (d, J=1.2Hz, 1H), 4.71 (d, J=12.3 Hz, 1H), 4.35 (m, 1H), 4.13 (d, J=12.5 Hz, 1H),3.96 (dd, J=4.4, 12.2 Hz, 1H), 3.65 (dd, J=4.4, 12.7 Hz, 1H), 3.12 (s,3H), 2.24 (m, 1H), 2.11 (m, 1H), 1.65 (s, 6H), 1.56 (t, J=3.1 Hz, 1H),1.50 (d, J=6.8 Hz, 6H)

Example 74[(1R,5S,6r)-6-(2,2-dimethyl-2,3-dihydro-11H-indole-1-carbonyl)-3-azabicyclo[3.1.0]hexan-3-yl][1-(propan-2-yl)-1H-imidazol-4-yl]methanone2,2-dimethylindoline

To a solution of 2,2-dimethyl-1,2-dihydro-3H-indol-3-one (270 mg, 1.67mmol) and trichloroalumane (223.33 mg, 1.67 mmol) in THF (5 mL) wasadded LiAlH₄ (95.47 mg, 2.51 mmol) at 0° C. under N₂. The reactionmixture was stirred at 20° C. under N₂ for 2 hours. TLC (PE:EtOAc=4:1)showed the reaction was completed. The reaction mixture was basifiedwith NaHCO₃ aq. to pH=8, extracted with EtOAC (10 mL×3), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-TLC (PE:EtOAc=4:1) to affordthe title compound (60 mg, 0.4076 mmol, 24.333% yield) (crude) as yellowoil.

tert-butyl(1R,5S,6r)-6-[(2,2-dimethyl-2,3,3a,7a-tetrahydro-1H-indol-1-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (92.62 mg, 0.41 mmol) in DCM (1 mL) were added HATU (233.71 mg,0.61 mmol) and Et₃N (0.11 mL, 0.82 mmol). The mixture was stirred at 20°C. for 10 minute under N₂. Then 2,2-dimethylindoline (60 mg, 0.41 mmol)was added. The resulting mixture was stirred at 20° C. for 16 h to givebrown mixture. The reaction mixture was poured into H₂O (10 mL) andextracted with EtOAc (10 mL×4). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give brown oil. The residue was purified by prep-TLC(PE:EtOAc=4:1) to afford the title compound (45 mg, 0.1262 mmol, 30.975%yield) as a brown oil.

(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(2,2-dimethyl-2,3,3a,7a-tetrahydro-1H-indol-1-yl)methanoneTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-[(2,2-dimethyl-2,3,3a,7a-tetrahydro-1H-indol-1-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(45 mg, 0.13 mmol) in DCM (4 mL) was added TFA (1 mL, 13.46 mmol). Theresulting mixture was stirred at 20 to 25° C. for 1 h. The reactionmixture was purged with N₂ to remove the solvent to afford the titlecompound (32 mg, 0.1248 mmol, 98.884% yield) as brown oil.

[(1R,5S,6r)-6-(2,2-dimethyl-2,3-dihydro-1H-indole-1-carbonyl)-3-azabicyclo[3.1.0]hexan-3-yl][1-(propan-2-yl)-1H-imidazol-4-yl]methanone

To a solution of 1-isopropylimidazole-4-carboxylic acid (25.02 mg, 0.16mmol) in DMF (1.5 mL) were added HATU (57.27 mg, 0.15 mmol), Et₃N (0.07mL, 0.50 mmol) and(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(2,2-dimethyl-2,3,3a,7a-tetrahydro-1H-indol-1-yl)methanoneTFA salt (32 mg, 0.12 mmol). The resulting mixture was stirred at 20 to25° C. for 12 hours to give green solution. The reaction mixture waspoured into H₂O (10 mL) and extracted with EtOAc (10 mL×4). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by prep-HPLC (NH₃). Theafforded flows were combined, concentrated to remove most of CH₃CN andlyophilized to afford the title compound (18 mg, 0.0459 mmol, 36.738%yield) as white solid.

LC-MS Method1: 393.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (s, 1H), 7.48 (s, 1H), 7.26-7.20(m, 1H), 7.18-7.13 (m, 2H), 7.00-6.95 (m, 1H), 4.78 (d, J=12.4 Hz, 1H),4.36 (td, J=6.8, 13.5 Hz, 1H), 4.22 (br d, J=12.5 Hz, 1H), 4.07 (dd,J=4.5, 12.3 Hz, 1H), 3.77 (dd, J=4.2, 13.3 Hz, 1H), 2.97 (br s, 2H),2.46 (dd, J=3.6, 7.2 Hz, 1H), 2.30 (br d, J=3.3 Hz, 1H), 1.93 (br s,1H), 1.56 (br s, 2H), 1.56-1.52 (m, 4H), 1.50 (d, J=6.6 Hz, 6H)

Example 75cyclopropyl{(1R,5S,6r)-3-[(1-isopropyl-1H-imidazol-4-yl)carbonyl]-3-azabicyclo[3.1.0]hex-6-yl}methanonetert-butyl(1R,5S,6r)-6-[cyclopropyl(hydroxy)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg,2.37 mmol) in THF (5 mL) was drop wise added bromo(cyclopropyl)magnesium(7.1 mL, 3.55 mmol) at 0° C. The mixture was stirred at 0° C. for 45min. The mixture was poured into H₂O (40 mL) slowly and extracted byEtOAc (20 mL×3). The organic phase was washed with brine (50 mL), driedover anhydrous Na₂SO₄, filtered and concentrated to give the titlecompound (600 mg, 2.36 mmol) as yellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.75-3.50 (m, 2H), 3.45-3.30 (m, 2H),2.75-2.55 (m, 2H), 1.57 (s, 2H), 1.44 (s, 9H), 1.10-0.90 (m, 1H),1.90-1.80 (m, 1H), 0.60-0.45 (m, 2H), 0.30-0.20 (m, 2H). tert-butyl(1R,5S,6r)-6-(cyclopropylcarbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[cyclopropyl(hydroxy)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(550 mg, 2.17 mmol) in DCM (11 mL) was added DMP (1.01 g, 2.39 mmol) at0° C. The mixture was stirred at 20° C. for 2 h. TLC (PE:EtOAc=3:1)showed the starting material (Rf=0.3) was consumed completely and a newspot (Rf=0.6) was detected. The mixture was poured into H₂O (30 mL)slowly, extracted by DCM (25 mL×3). The organic phase was washed withsaturated NaHCO₃ (30 mL×2) and brine (35 mL×1), dried over anhydrousNa₂SO₄ and concentrated to give a residue. The residue was purified bySiO₂ flash column (PE:EtOAc=10:1-1:1) to afford the title compound (280mg, 1.11 mmol, 51.3% yield) as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.70 (d, J=11.2 Hz, 1H), 3.61 (d,J=11.2 Hz, 1H), 3.45-3.40 (m, 2H), 2.10 (s, 2H), 2.10-2.00 (m, 1H), 1.92(s, 1H), 1.46 (s, 9H), 1.10-1.00 (m, 2H), 0.95-0.90 (m, 2H). (1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(cyclopropyl)methanone

To a solution of tert-butyl(1R,5S,6r)-6-(cyclopropylcarbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(80 mg, 0.32 mmol) in DCM (5 mL) was added TFA (1 mL, 13.4 mmol). Themixture was stirred at 25° C. for 2 h. TLC (PE:EtOAc=3:1) showed a newspot (Rf=0) was detected. The mixture was concentrated to afford thetitle compound (80 mg, 0.52 mmol) as a yellow oil. The crude was usedfor next directly.

cyclopropyl{(1R,5S,6r)-3-[(1-isopropyl-1H-imidazol-4-yl)carbonyl]-3-azabicyclo[3.1.0]hex-6-yl}methanone

To a solution of(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(cyclopropyl)methanone (75 mg, 0.5mmol) and DIPEA (0.41 mL, 2.48 mmol) in DMF (2 mL) was added HATU (189mg, 0.5 mmol) and 1-isopropylimidazole-4-carboxylic acid (76.4 mg, 0.5mmol). The mixture were stirred at 20° C. for 16 h. The mixture wasdiluted with H₂O (50 mL), extracted by EtOAc (25 mL×3). The organicphase was washed by brine (50 mL×3), dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue. The residue was purified byPrep-HPLC (NH₃) to afford the title compound (7 mg, 0.024 mmol, 4.91%yield) as a white solid.

LC-MS Method1: 288.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.68 (d, J=1.5 Hz, 1H) 7.48 (d,J=1.4 Hz, 1H) 4.75 (d, J=12.1 Hz, 1H) 4.36 (dt, J=13.4, 6.7 Hz, 1H) 4.17(d, J=12.8 Hz, 1H) 3.95 (dd, J=12.2, 3.9 Hz, 1H) 3.63 (dd, J=12.6, 4.1Hz, 1H) 2.26 (dt, J=7.1, 3.5 Hz, 1H) 2.16 (dt, J=7.2, 3.5 Hz, 1H)1.98-2.06 (m, 1H) 1.93 (t, J=3.0 Hz, 1H) 1.51 (d, J=6.6 Hz, 6H)1.02-1.08 (m, 2H) 0.88-0.94 (m, 2H)

Example 76(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(2-thienylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]methanonetert-butyl(1R,5S,6r)-6-(2-thienylcarbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of 2-bromothiophene (0.28 mL, 2.84 mmol) in THF (5 mL) wasadded n-BuLi (1.42 mL, 3.55 mmol) dropwise at −78° C. The reactionmixture was stirred at −78° C. for 1 h. Then tert-butyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg,2.37 mmol) was added at −78° C. The resulting mixture was stirred at 25°C. for 30 min. The reaction mixture was diluted with H₂O (10 mL) andthen extracted with EtOAc (10 mL×2). The combined organic layers weredried over Na₂SO₄ and concentrated in vacuum to give crude oil. Thecrude oil was purified by flash column (0-30% EtOAc in PE) to give thetitle compound (30 mg, 0.1023 mmol, 4.3205% yield) as pale yellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.75 (s, 1H), 7.60 (s, 1H), 7.09 (s,1H), 3.80-3.50 (m, 2H), 3.50-3.40 (m, 2H), 2.31 (s, 1H), 2.23 (brs, 2H),1.40 (s, 9H).

(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(2-thienyl)methanone TFA salt

The mixture of tert-butyl(1R,5S,6r)-6-(2-thienylcarbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(30 mg, 0.10 mmol) in DCM (0.50 mL) and TFA (0.1 mL, 0.10 mmol) wasstirred at 25° C. for 2 hr. The reaction mixture was concentrated todryness to give the title compound (19 mg, 0.0983 mmol, 96.139% yield)as yellow oil.

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(2-thienylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(2-thienyl)methanone TFA salt (19mg, 0.10 mmol) in Pyridine (0.50 mL) were added EDCI (22.61 mg, 0.12mmol) and 1-isopropylimidazole-4-carboxylic acid (15.16 mg, 0.10 mmol).The resulting mixture was stirred at 20° C. for 16 hr. The reactionmixture was diluted with H₂O (5 mL) and then extracted with EtOAc (5mL×3). The combined organic layers were washed with brine (10 mL), thendried over Na₂SO₄ and concentrated in vacuum to give the residue. Theresidue was purified by prep-TLC (EtOAc/MeOH=20/1, 0.05% NH₃.H₂O) toafford the title compound (5 mg, 0.0152 mmol, 15.439% yield) as whitesolid.

¹H NMR (400 MHz, CD₃OD) δ=8.02 (d, J=3.0 Hz, 1H), 7.84 (d, J=4.8 Hz,1H), 7.77 (br d, J=7.5 Hz, 2H), 7.22-7.18 (m, 1H), 4.50 (br d, J=8.3 Hz,2H), 4.14 (br d, J=13.1 Hz, 1H), 4.01 (br s, 1H), 3.71 (br s, 1H), 2.59(s, 1H), 2.38 (br d, J=17.8 Hz, 2H), 1.51 (d, J=6.5 Hz, 6H), 1.46 (s,1H), 1.44-1.42 (m, 1H).

Example 77(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4-methyl-2-thienyl)carbonyl]-3-azabicyclo[3.1.0]hex-3-yl}methanonetert-butyl(1R,5S,6r)-6-[hydroxy(4-methyl-2-thienyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(compound 1) andtert-butyl(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(4-methyl-2thienyl)methanone (compound 2)

To a solution of 3-methylthiophene (0.24 mL, 2.55 mmol) in THF (5 mL)was dropwise added 2.5 M n-BuLi in n-Hexane (1.02 mL, 2.55 mmol) at −78°C. The mixture was stirred at −78° C. for 0.5 hour under N₂. Then,tert-butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate(742.43 mg, 3.51 mmol) was added at −78° C. The resulting solution waswarmed to 25° C. and stirred for 1 hour to give a brown solution. Thereaction mixture was diluted with EtOAc and quenched with saturatedNH₄Cl solution carefully. The resulting mixture was poured into H₂O (10mL) and extracted with EtOAc (10 mL×3). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product was purified by flash column(PE:EtOAc=30:1) to give the title compound 1 (660 mg, 2.133 mmol, 83.76%yield) as a yellow oil and the title compound 2 (100 mg, 0.3253 mmol,12.774% yield) as a yellow solid.

tert-butyl(1R,5S,6r)-6-[(4-methyl-2-thienyl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[hydroxy(4-methyl-2-thienyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(660 mg, 2.13 mmol) in DCM (8 mL) was added DMP (1357.05 mg, 3.2 mmol)at 0° C. The mixture was stirred at 25° C. for 2 hours to give a whitesuspension. The reaction mixture was poured into H₂O (10 mL) andextracted with EtOAc (10 mL×3). The combined organic layers were washedwith NaHCO₃.aq. (20 mL) and Na₂SO₃ aq. (10 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crudeproduct. The crude product was purified by flash column chromatography(PE:EtOAc=30:1) to give the title compound (500 mg, 1.6265 mmol, 76.253%yield).

(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(4-methyl-2-thienyl)methanone TFAsalt

To a solution of tert-butyl(1R,5S,6r)-6-[(4-methyl-2-thienyl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.33 mmol) in DCM (5 mL) was added TFA (0.75 mL, 9.76 mmol).The resulting mixture was stirred at 25° C. for 2 hours to give a yellowsolution. The reaction mixture was evaporated in vacuum to give thetitle compound (60 mg, 0.2894 mmol, 88.98% yield) as a yellow oil. Itwas directly used in the next step.

(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4-methyl-2-thienyl)carbonyl]-3-azabicyclo[3.1.0]hex-3-yl}methanone

To a solution of(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(4-methyl-2-thienyl)methanone TFAsalt (130 mg, 0.63 mmol) in DMF (4 mL) were added HATU (359.63 mg, 0.94mmol) and Et₃N (0.16 mL, 1.25 mmol). The mixture was stirred at 25° C.for 10 min under N₂. Then, 1-isopropylimidazole-4-carboxylic acid(193.37 mg, 1.25 mmol) in DMF (2 mL) was added, the resulting mixturewas stirred at 25° C. for 16 hours to give a yellow mixture. Thereaction mixture was poured into H₂O (10 mL) and extracted with EtOAc(10 mL×3). The combined organic layers were washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the crude product. The crude product was purified by Prep-HPLC(NH₃) and lyophilized to give the title compound (200 mg, 0.5823 mmol,92.857% yield) as a yellow solid.

LC-MS Method1: 344.2 [M+H]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.72 (d, J=1.3 Hz, 1H), 7.59 (d, J=1.0Hz, 1H), 7.49 (d, J=1.3 Hz, 1H), 7.24 (s, 1H), 4.79 (d, J=12.3 Hz, 1H),4.38 (spt, J=6.7 Hz, 1H), 4.23 (d, J=12.8 Hz, 1H), 4.03 (dd, J=4.0, 12.3Hz, 1H), 3.71 (dd, J=3.8, 12.8 Hz, 1H), 2.51-2.41 (m, 1H), 2.37-2.31 (m,2H), 2.29 (s, 3H), 1.52 (d, J=6.8 Hz, 6H)

Example 78(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4-methoxy-2-thienyl)carbonyl]-3-azabicyclo[3.1.0]hex-3-yl}methanonetert-butyl(1R,5S,6r)-6-[hydroxy(4-methoxy-2-thienyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of 3-methoxy thiophen (0.18 mL, 2.13 mmol) in THF (3 mL)was added 2.5 M n-BuLi in n-Hexane (0.85 mL, 2.13 mmol) at −78° C. Themixture was stirred at −78° C. for 0.5 h under N₂. tert-butyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (300 mg,1.42 mmol) was added at −78° C. The resulting mixture was stirred at 20to 25° C. for 2 h. The reaction mixture was poured into sat. NH₄Cl aq.(2 mL) and the aqueous layer was extracted with EtOAc (10 mL×4). Thecombined organic layers were washed with sat. aq. (10 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by flash column (PE to 30% EtOAc in PE) to affordthe title compound (380 mg, 1.1677 mmol, 82.231% yield) as a yellow gum.

tert-butyl (1R5S,6r)-6-[(4-methoxy-2-thienyl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[hydroxy(4-methoxy-2-thienyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(380 mg, 1.17 mmol) in THF (4 mL) was added MnO₂ (507.61 mg, 5.84 mmol).The mixture was stirred at 50° C. for 16 h. TLC (PE:EtOAc=2:1) showednew spots and the starting material was remained. The mixture was thenfiltered and the filtrate was concentrated in vacuum. The residue waspurified by prep-TLC (PE:EtOAc=2:1) to afford the title compound (60 mg,0.1855 mmol, 15.888% yield) as a colorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.43 (d, J=1.8 Hz, 1H), 6.64 (d, J=1.6Hz, 1H), 3.85 (s, 3H), 3.75 (br d, J=11.4 Hz, 1H), 3.65 (br d, J=10.9Hz, 1H), 3.50 (br d, J=8.9 Hz, 2H), 2.29 (s, 3H), 1.48 (s, 9H)(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(4-methoxy-2-thienyl)methanone TFAsalt

To a solution of tert-butyl(1R,5S,6r)-6-[(4-methoxy-2-thienyl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(70 mg, 0.22 mmol) in DCM (3.5 mL) was added 2,2,2-trifluoroacetic acid(0.35 mL, 4.57 mmol). The resulting mixture was stirred at 20 to 25° C.for 1 h. TLC (PE:EtOAc=2:1) showed the reaction was completed (Rf=0).The mixture was concentrated by purging with N₂ to afford the titlecompound (48 mg, 0.2150 mmol, 99.318% yield) as a purple solid.

(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4-methoxy-2-thienyl)carbonyl]-3-azabicyclo[3.1.0]hex-3-yl}methanone

To a solution of 1-isopropylimidazole-4-carboxylic acid (33.14 mg, 0.21mmol) in Pyridine (2 mL) were added EDCI (61.81 mg, 0.32 mmol) and(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(4-methoxy-2-thienyl)methanone TFAsalt (48 mg, 0.21 mmol) at 20 to 25° C. for 2 h. The reaction mixturewas concentrated directly. The residue was purified by prep-HPLC (NH₃)to afford crude product. The crude product was purified by prep-TLC(DCM:MeOH=10:1) to afford the title compound (5.73 mg, 0.0159 mmol,7.4158% yield) as a white solid.

LC-MS Method1: 360.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.72 (s, 1H), 7.54-7.48 (m, 1H), 7.40(d, J=1.5 Hz, 1H), 6.63 (d, J=1.8 Hz, 1H), 4.79 (d, J=12.3 Hz, 1H), 4.38(td, J=6.9, 13.3 Hz, 1H), 4.23 (d, J=12.5 Hz, 1H), 4.04 (dd, J=4.0, 12.0Hz, 1H), 3.83 (s, 3H), 3.71 (dd, J=3.8, 12.5 Hz, 1H), 2.46 (br d, J=3.3Hz, 1H), 2.35 (br d, J=6.3 Hz, 1H), 2.32-2.27 (m, 1H), 1.52 (d, J=6.5Hz, 8H)

Example 79(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4-methyl-1,3-thiazol-2-yl)carbonyl]-3-azabicyclo[3.1.0]hex-3-yl}methanonetert-butyl(1R,5S,6r)-6-[hydroxy(4-methyl-1,3-thiazol-2-yl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of 2-bromo-4-methyl-1,3-thiazole (74.48 uL, 0.71 mmol) inTHF (2 mL) was added 2.5 M n-BuLi in n-Hexane (0.34 mL, 0.86 mmol) at−78° C. The mixture was stirred at −78° C. for 0.5 h under N₂. Then tothe reaction mixture added tert-butyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (210.89 mg,1 mmol) at −78° C. The resulting solution was warmed to 25° C. andstirred for 1 h to give a brown solution. LCMS showed the desire MS. Thereaction mixture was poured into NH₄Cl aq. (20 mL) and extracted withEtOAc (20 mL×4). The combined organic layers were washed with brine (50mL×2), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude product was purified by flash column (PE to 20%EtOAc in PE) to give the title compound (220 mg, 0.7087 mmol, 99.396%yield) as brown oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (s, 1H), 5.00-4.85 (m, 1H), 4.06(t, J=10.8 Hz, 2H), 3.90-3.75 (m, 2H), 2.85 (s, 3H), 2.25-2.00 (m, 2H),1.84 (s, 9H), 1.70-1.60 (m, 1H), 1.55-1.50 (m, 1H). tert-butyl(1R,5S,6r)-6-[(4-methyl-1,3-thiazol-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[hydroxy(4-methyl-1,3-thiazol-2-yl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(220 mg, 0.71 mmol) in DCM (4 mL) was added DMP (450.91 mg, 1.06 mmol)at 0° C. The mixture was stirred at 25° C. for 3 h to give whitesuspension. The reaction mixture was filtered. The filtrate was washedwith NaHCO₃ aq. (50 mL×2) and Na₂SO₃.aq. (50 mL×2), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the titlecompound (220 mg, 0.7134 mmol, 100.65% yield) as brown oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.27 (s, 1H), 3.78 (d, J=11.2 Hz, 1H),3.72 (d, J=11.2 Hz, 1H), 3.55-3.45 (m, 2H), 3.15-3.10 (m, 1H), 2.57 (s,3H), 2.35 (brs, 2H), 1.48 (s, 9H).

(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(4-methyl-1,3-thiazol-2-yl)methanoneTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-[(4-methyl-1,3-thiazol-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.32 mmol) in DCM (5 mL) was added TFA (1. mL, 0.32 mmol). Themixture was stirred at 25° C. for 30 min to give brown solution. TLC(PE:EtOAc=3:1) showed the reaction was completed. The reaction mixturewas concentrated directly to give the title compound (100 mg, 0.3103mmol, 95.687% yield, TFA salt) as brown oil.

(1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4-methyl-1,3-thiazol-2-yl)carbonyl]-3-azabicyclo[3.1.0]hex-3-yl}methanone

To a solution of 1-isopropylimidazole-4-carboxylic acid (47.83 mg, 0.31mmol) in DMF (2 mL) were added HATU (142.34 mg, 0.37 mmol) and DIPEA(200.5 mg, 1.55 mmol). The mixture was stirred at 25° C. for 20 min.Then(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(4-methyl-1,3-thiazol-2-yl)methanoneTFA salt (100 mg, 0.31 mmol, TFA salt) was added. The mixture wasstirred at 25° C. for 2 h to give brown solution. The mixture wasstirred at 25° C. for 12 h to give brown solution. The reaction mixturewas concentrated directly. The residue was purified by prep-HPLC (NH₃)to give the title compound (20.22 mg, 0.0587 mmol, 18.921% yield) asyellow solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.72 (1H, d, J=1.51 Hz), 7.48 (1H,d, J=1.51 Hz), 7.24 (1H, d, J=0.75 Hz), 4.81 (1H, d, J=12.30 Hz),4.33-4.43 (1H, m), 4.28 (1H, d, J=13.05 Hz), 4.07 (1H, dd, J=12.30, 4.02Hz), 3.72 (1H, dd, J=12.80, 4.02 Hz), 3.12 (1H, t, J=3.14 Hz), 2.53 (4H,d, J=0.75 Hz), 2.40 (1H, dt, J=7.09, 3.61 Hz), 1.52 (6H, d, J=6.53 Hz)

Example 80(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(2-pyridinylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]methanonebromo(2-pyridinyl)magnesium

To a solution of 2-bromopyridine (0.61 mL, 6.33 mmol) in THF (10 mL) wasadded chloro(isopropyl)magnesium (3.2 mL, 6.33 mmol) at 15° C. Thereaction mixture was stirred at 0° C. for 4 hr to give the titlecompound as a mixture. The reaction mixture was used for the next stepwithout further purification.

tert-butyl(1R,5S,6r)-6-[hydroxy(2-pyridinyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.61 mL,1.42 mmol) in THF (6 mL) was added bromo(2-pyridinyl)magnesium (3.2 mL,2.13 mmol) at 15° C. The reaction mixture was stirred at 0° C. for 4 hrto give a brown mixture. TLC (PE/EA=1:2) showed a new spot. The reactionmixture was quenched with H₂O (30 mL) and extracted with EtOAc (30mL×2). The organic layer was washed with brine (30 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by silica gel column(PE/EA=1:2) to give the title compound (460 mg, 1.5842 mmol, 111.56%yield) as light yellow gum.

¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (dd, J=4.4, 0.8 Hz, 1H), 7.78 (t, J=5.6Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.30-7.20 (m, 1H), 5.41 (d, J=4.8 Hz,1H), 4.27 (t, J=5.6 Hz, 1H), 3.40-3.20 (m, 4H), 1.62 (brs, 2H), 1.37 (s,9H), 1.85-1.75 (m, 1H).

tert-butyl(1R,5S,6r)-6-[(2-pyridinyl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[hydroxy(2-pyridinyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(460 mg, 1.58 mmol) in DCM (9.6442 mL) was added DMP (671.94 mg, 1.58mmol) at 15° C. The reaction mixture was stirred at 15° C. for 20 min togive a white mixture. TLC (PE/EA=1:1) showed a new spot. The reactionmixture was quenched with NaHCO₃ (30 mL) and extracted with DCM (30mL×2). The organic layer was washed with brine (30 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by silica gel column(PE/EA=1:1) to give the title compound (340 mg, 1.1792 mmol, 74.431%yield) as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (dd, J=4.4, 0.8 Hz, 1H), 8.02 (t, J=5.6Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.70-7.60 (m, 1H), 3.57 (d, J=11.4 Hz,1H), 3.50-3.25 (m, 3H), 3.25-3.20 (m, 1H), 2.22 (brs, 2H), 1.41 (s, 9H),1.85-1.75 (m, 1H).

(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(2-pyridinyl)methanone TFA salt

To a solution of tert-butyl(1R,5S,6r)-6-[(2-pyridinyl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(58 mg, 0.20 mmol) in DCM (1.5 mL) was added TFA (0.02 mL, 0.20 mmol).The reaction mixture was stirred at 20° C. for 2 hr to give a colorlessmixture. The reaction mixture was concentrated under reduced pressure togive the title compound. It was used for the next step directly.

LC-MS Method1: 0.268 min, MS (m/z): 189.0 (M+H⁺).

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(2-pyridinylcarbonyl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(2-pyridinyl)methanone TFA salt(37 mg, 0.20 mmol) in Pyridine (1.5 mL) were added1-isopropylimidazole-4-carboxylic acid (45.46 mg, 0.29 mmol) and EDCI(56.52 mg, 0.29 mmol). The reaction mixture was stirred at 20° C. for 16hr. The solution was purified by prep-HPLC (NH₃) and lyophilized toafford the title compound (7.52 mg, 11.79% yield) as yellow solid.

LC-MS Method1: 0.363 min, MS (m/z): 325.2 (M+H⁺).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.68 (d, J=4.77 Hz, 1H), 8.02 (d,J=7.78 Hz, 1H), 7.81-7.86 (m, 1H), 7.71 (s, 1H), 7.45-7.49 (m, 2H), 4.79(d, J=12.30 Hz, 1H), 4.37 (dt, J=13.36, 6.74 Hz, 1H), 4.28 (d, J=12.80Hz, 1H), 4.08 (dd, J=12.17, 3.89 Hz, 1H), 3.73 (dd, J=12.80, 4.02 Hz,1H), 3.45 (t, J=3.01l Hz, 1H), 2.44-2.49 (m, 1H), 2.36 (dt, J=7.28, 3.64Hz, 1H), 1.52 (d, J=6.53 Hz, 6H)

Example 81[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone

ethyl (2E)-2-hydrazonopropanoate

Hydrazine hydrate (0.86 g, 17.22 mmol) was slowly added to a mixture ofglacial HOAc (1.4 mL, 24.5 mmol) and H₂O (1.4 mL, 77.78 mmol) at 0° C.Then ethyl 2-oxopropanoate (0.95 mL, 8.61 mmol) was added at roomtemperature. MeOH (0.5 mL) was added in order to obtain a homogeneoussolution. The mixture was stirred at 25° C. for 6 h to give yellowsolution. TLC (PE:EtOAc=1:1) showed the reaction was completed. Thereaction mixture was removed under reduced pressure. H₂O (40 mL) wasadded to the residue and the mixture was extracted with EtOAc (30 mL×4).The combined organic phases were washed with saturated sodium hydrogencarbonate (30 mL×2), saturated brine (40 mL×2) and dried over Na₂SO₄.The solvent was removed under reduced pressure. The crude product waspurified by flash column chromatography (PE to 20% EtOAc in PE) to givethe title compound (930 mg, 7.1456 mmol, 82.975% yield) as colorlessoil.

LC-MS Method1 0.348 min, MS (m/z) 130.8 [M+H].¹H NMR (400 MHz, CHLOROFORM-d) δ=5.93 (brs, 2H), 4.28 (q, J=6.8 Hz, 2H),1.99 (s, 3H), 1.37 (t, J=6.8 Hz, 3H).

ethyl3-benzyl-6-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate

To a solution of ethyl (2E)-2-hydrazonopropanoate (2.5 g, 19.21 mmol) in1,4-Dioxane (30 mL) was added MnO₂ (10.02 g, 115.25 mmol). The mixturewas stirred at 20° C. for 1.5 h and then filtered through a pad ofCelite. To the filtrate was added 1-benzyl-1H-pyrrole-2,5-dione (3.6 g,19.21 mmol). The reaction was stirred at 20° C. for 2 h and at 100° C.for 16 h to give yellow solution. TLC (PE:EtOAc=5:1) showed the reactionwas completed.

The reaction mixture was concentrated directly. The crude product waspurified by flash column (PE to 10% EtOAc in PE). The afforded solid wastriturated with EtOAc/PE (2 mL/20 mL) and dried in air to give the titlecompound (1.28 g, 4.4551 mmol, 23.193% yield) as colorless solid.

LC-MS Method1 0.827 min, MS (m/z) 287.9 [M+H⁺].

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.45-7.25 (m, 5H), 4.57 (s, 2H), 4.15(q, J=6.8 Hz, 2H), 2.89 (s, 2H), 1.25 (t, J=6.8 Hz, 3H), 1.14 (s, 3H).ethyl 3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylate

To a solution of ethyl3-benzyl-6-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate (2.5g, 8.7 mmol) (crude) in THF (25 mL) was added BORANE DIMETHYL SULFIDECOMPLEX (3.48 mL, 34.81 mmol) at 25° C. The mixture was stirred at 70°C. for 2 h to give colorless suspension. TLC (PE:EtOAc=5:1) showed thereaction was completed. The reaction mixture was added dropwise intoMeOH/HCl (12 N) (8:1=5 mL) and the mixture was stirred for 30 min. Thenthe mixture was concentrated directly. The crude product was purified byflash column (PE to 10% EtOAc in PE) to the title compound (600 mg,2.3136 mmol, 26.588% yield) as colorless oil.

LC-MS Method1 0.781 min, MS (m/z) 260.1 [M+H⁺].¹H NMR (400 MHz, CHLOROFORM-d) δ=7.50-7.30 (m, 5H), 4.10 (q, J=6.8 Hz,2H), 4.05 (s, 2H), 3.36 (dt, J=12.0, 1.2 Hz, 2H), 2.98 (d, J=5.2 Hz,1H), 2.88 (d, J=5.2 Hz, 1H), 2.45-2.40 (m, 1H), 2.20-2.10 (m, 1H), 1.40(s, 9H), 1.25 (t, J=6.8 Hz, 3H), 0.70 (s, 1H).

[(1R,5S,6r)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]methanol

To a solution of ethyl3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylate (600 mg, 2.31mmol) in THF (8 mL) was added LiAlH4 (131.87 mg, 3.47 mmol) at 0° C. Themixture was stirred at 0° C. for 10 min to give white suspension. TLC(PE:EtOAc=5:1) showed the reaction was completed. To there actionmixture was added H₂O (0.15 mL), 1N NaOH aq (0.15 mL), H₂O (0.5 ml)continuously and filtered. The filtrate was concentrated to givecolorless oil. The crude product was purified by flash columnchromatography (PE to 30% EtOAc in PE) to give the title compound (270mg, 1.2425 mmol, 53.703% yield) colorless oil.

LC-MS Method1 1.643 min, MS (m/z) 218.2 [M+H⁺].¹H NMR (400 MHz, CHLOROFORM-d) δ=7.55-7.50 (m, 2H), 7.45-7.40 (m, 3H),4.03 (s, 2H), 3.40-3.25 (m, 2H), 3.30 (s, 2H), 3.00-2.90 (m, 2H),1.60-1.55 (m, 2H), 1.27 (s, 3H). The relative configuration wasdetermined by NoE experiments.

tert-butyl(1R,5S,6r)-6-(hydroxymethyl)-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of[(1R,5S,6r)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]methanol (100mg, 0.4600 mmol) in MeOH (3 mL) was added Pd(OH)₂ (30 mg, 0.4600 mmol).The mixture was stirred at 20° C. under H₂ (15 psi) for 12 h to giveblack solution. TLC (PE:EtOAc=1:1) showed the reaction was completed.The reaction mixture was filtered and the filtrate was concentrated. Theresidue was diluted with DCM (3 mL) and di-tert-butyl dicarbonate(150.65 mg, 0.6900 mmol) was added into the solution. The mixture wasstirred at 20° C. for 30 min to give colorless solution. The reactionmixture was concentrated directly. The crude product was purified byflash column (PE to 30% EtOAc in PE) to give the title compound (35 mg,0.1540 mmol, 33.462% yield) as white solid.

LC-MS Method1 0.710 min, MS (m/z) 171.8 [M−tBu+H⁺].

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.60-3.45 (m, 2H), 3.45-3.35 (m, 2H),1.50-1.45 (m, 2H), 1.49 (s, 9H), 1.04 (s, 3H). tert-butyl(1R,5S,6r)-6-formyl-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-(hydroxymethyl)-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate(70 mg, 0.3100 mmol) in DCM (2 mL) was added DMP (143.68 mg, 0.3400mmol) at 0° C. The mixture was stirred at 20° C. for 2 h to give whitesuspension. TLC (PE:EtOAc=1:1) showed the reaction was completed. Thereaction mixture was poured into H₂O (20 mL) and extracted with EtOAc(20 mL×4). The combined organic layers were washed with NaHCO₃.aq. (50mL), Na₂SO₃.aq. (50 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give the title compound (62 mg, 0.2752 mmol,89.366% yield) as yellow gum.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.96 (s, 1H), 3.70-3.55 (m, 2H), 3.48(d, J=11.4 Hz, 1H), 3.40 (d, J=11.4 Hz, 1H), 2.15 (d, J=2.0 Hz, 1H),1.45 (s, 9H), 1.72 (s, 3H). tert-butyl(1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-formyl-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (62mg, 0.2800 mmol) in EtOH (1.5 mL) were added HOAc (15.73 uL, 0.2800mmol), KOAc (26.97 mg, 0.2800 mmol) and hydroxylamine hydrochloride(0.01 mL, 0.3300 mmol). The mixture was stirred at 20° C. for 2 h togive yellow suspension. TLC (PE:EtOAc=3:1) showed the reaction wascompleted. The reaction mixture was poured into H₂O (20 mL) andextracted with EtOAc (15 mL×4). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the title compound (65 mg, 0.2705 mmol, 98.286%yield) as yellow solid.

LC-MS Method1 0.727 min, MS (m/z) 185.0 [M−tBu+H⁺].

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.03 (s, 1H), 3.65-3.50 (m, 2H), 3.46(d, J=11.2 Hz, 1H), 3.39 (d, J=11.2 Hz, 1H), 1.80 (d, J=2.4 Hz, 2H),1.45 (s, 9H), 1.15 (s, 3H). tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate(65 mg, 0.2700 mmol) in DMF (1.5 mL) was added NCS (39.73 mg, 0.3000mmol). The mixture was stirred at 20° C. for 14 h to give brownsolution. The mixture was poured into H₂O (15 mL) and extracted withEtOAc (15 mL×5). The combined organic layer was washed with brine (50mL), dried over Na₂SO₄ and concentrated to dryness to give the titlecompound (70 mg, 0.2548 mmol, 94.193% yield) as yellow oil.

LC-MS Method1 0.802 min, MS (m/z) 218.9 [M−tBu+H⁺].

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.55 (s, 1H), 3.66-3.55 (m, 2H), 3.47(d, J=9.0 Hz, 1H), 3.39 (d, J=9.0 Hz, 1H), 2.15-2.08 (m, 2H), 1.44 (s,9H), 1.22 (s, 3H). tert-butyl(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.1]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate(70 mg, 0.2500 mmol) in DMF (1.5 mL) were added Et₃N (0.13 mL, 0.7600mmol) and 2-methylprop-1-ene (0.48 mL, 0.7600 mmol, 2.4 M in THF). Themixture was stirred at 20° C. for 12 h to give brown solution. Themixture was poured into H₂O (15 mL) and extracted with EtOAc (15 mL×5).The combined organic layer was washed with brine (50 mL), dried overNa₂SO₄ and concentrated to dryness to give the title compound (70 mg,0.2378 mmol, 93.325% yield) as yellow oil.

LC-MS Method1 0.810 min, MS (m/z) 295.1 [M+H⁺].

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.60-3.55 (m, 2H), 3.46 (d, J=8.7 Hz,1H), 3.38 (d, J=8.7 Hz, 1H), 2.64 (s, 2H), 2.00-1.92 (m, 2H), 1.45 (s,9H), 1.36 (s, 6H), 1.16 (s, 3H).(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hexaneTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate(70 mg, 0.2400 mmol) in DCM (5 mL) was added TFA (1 mL, 13.46 mmol). Themixture was stirred at 20° C. for 30 min to give yellow solution. Thereaction mixture was concentrated directly to give the title compound(70 mg crude) as yellow oil.

LC-MS Method1 0.268 min, MS (m/z) 194.9 [M+H⁺].¹H NMR (400 MHz, DIMETHYL SUlFOXIDE-d6) δ ppm 9.58 (brs, 1H), 8.85 (brs,1H), 3.65-3.50 (m, 2H), 3.20-3.10 (m, 2H), 2.68 (s, 2H), 2.25 (m, 2H),1.25 (s, 6H), 1.18 (s, 3H).

[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone

To a solution of 1-isopropylimidazole-4-carboxylic acid (61.11 mg,0.4000 mmol) in DMF (2 mL) were added HATU (179.08 mg, 0.4700 mmol),Et₃N (0.2 mL, 1.44 mmol),(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hexaneTFA salt (70 mg, 0.3600 mmol). The mixture was stirred at 20° C. for 12h to give brown solution. The reaction mixture was concentrateddirectly. The residue was purified by prep-HPLC (NH₃). The affordedflows were combined, concentrated to remove most of CH₃CN andlyophilized to give the title compound (11.6 mg, 0.0351 mmol, 9.7431%yield) as brown solid.

LC-MS Method1 0.610 min, MS (m/z) 331.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.69 (1H, s), 7.48 (1H, s),4.17-4.44 (3H, m), 3.79-3.95 (2H, m), 2.66 (2H, d, J=1.63 Hz), 2.12-2.19(1H, m), 1.99-2.05 (1H, m), 1.51 (6H, dd, J=6.69, 1.56 Hz), 1.38 (6H,s), 1.19 (3H, d, J=1.75 Hz) Example 82(1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]methanone

(1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 1-cyclopropyl-1H-imidazole-4-carboxylic acid (14.81 mg,0.10 mmol) in Pyridine (0.75 mL) was added EDCI (27.98 mg, 0.15 mmol).The mixture was stirred for 20 minute. Then(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hexaneTFA salt; (30 mg, 0.10 mmol) was added. The mixture was stirred at 25°C. for 1 h. The reaction mixture was concentrated directly. The residuewas purified by prep-HPLC (NH₃). The afforded flows were combined,concentrated to remove most of CH₃CN and lyophilized to afford the titlecompound (9.93 mg, 0.0302 mmol, 31.073% yield) as a yellow gum.

LC-MS Method2 3.650 min, MS (m/z) 329.2 [M+H]+¹H NMR (400 MHz, CHLOROFORM-d) δ=7.66 (d, J=1.5 Hz, 1H), 7.51 (d, J=1.3Hz, 1H), 4.32-4.19 (m, 2H), 3.91-3.78 (m, 2H), 3.37 (tt, J=3.8, 7.2 Hz,1H), 2.66 (s, 2H), 2.14 (dd, J=4.9, 8.2 Hz, 1H), 2.06-1.96 (m, 1H), 1.38(s, 7H), 1.18 (s, 3H), 1.09-0.96 (m, 4H)

Example 83[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone

To a solution of 1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylic acid(42.77 mg, 0.2600 mmol) in DMF (1.5 mL) were added HATU (127.14 mg,0.3300 mmol) and DIPEA (0.21 mL, 1.29 mmol). The mixture was stirred for30 min. Then(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hexaneTFA salt (50 mg, 0.2600 mmol) was added. The mixture was stirred at 25°C. for 3 h to give brown solution. The reaction mixture was concentrateddirectly. The residue was purified by prep-HPLC (NH₃) to give the titlecompound (33.31 mg, 0.0973 mmol, 37.794% yield) as brown solid.

LC-MS Method1: 343.3 [M+H⁺]

¹H NMR (400 MHz, DMSO-d₆) δ=7.71 (s, 1H), 7.53 (d, J=1.2 Hz, 1H),4.32-4.20 (m, 2H), 3.89-3.80 (m, 2H), 2.66 (s, 3H), 2.16-1.99 (m, 2H),1.57 (s, 3H), 1.37 (s, 6H), 1.17 (s, 3H), 1.33-1.31 (m, 2H), 0.94-0.91(m, 2H).

Example 84(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonetert-butyl(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate(300 mg, 1.09 mmol) was added gradually to a solution ofmethylenecyclopropane (0.24 mL, 9.96 mmol) in THF (13.469 mL). Then,Et₃N (0.46 mL, 3.28 mmol) was added. The reaction mixture was stirred at0° C. for 16 hr to give a yellow solution. The reaction mixture wasdiluted with H₂O (30 mL) and extracted with EtOAc (30 mL×2). Thecombined organic layer was dried over Na₂SO₄ and concentrated in vacuumto give a residue. The residue was purified by silica column (PE/EA=2:1)to give the title compound (200 mg, 0.6841 mmol, 62.647% yield) as whitesolid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.65-3.55 (m, 2H), 3.47 (d, J=11.2 Hz,1H), 3.39 (d, J=11.2 Hz, 1H), 2.96 (s, 2H), 2.10-1.95 (m, 2H), 1.48 (s,9H), 1.20 (s, 3H), 1.15-1.05 (m, 2H), 0.75-0.65 (m, 2H).6-[(1R,5S,6r)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-eneTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(200 mg, 0.6800 mmol) in DCM (11.901 mL) was added 2,2,2-trifluoroaceticacid (0.05 mL, 0.6800 mmol). The reaction mixture was stirred at 10° C.for 1 hr to give a yellow solution. TLC (PE/EA=1:1) showed a new spot.The reaction mixture was evaporated in vacuum to give the title compound(200 mg, 0.6530 mmol, 95.458% yield) as yellow oil.

(1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

A 100 ml round-bottom flask was charged with1-isopropylimidazole-4-carboxylic acid (50.34 mg, 0.3300 mmol), HATU(149.78 mg, 0.3900 mmol), N-ethyl-N-isopropylpropan-2-amine (0.17 mL,0.9800 mmol) and DMF (1.6108 mL). After stirred for 30 min,6-[(1R,5S,6r)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-eneTFA salt (100 mg, 0.3300 mmol) was added. The reaction mixture wasstirred at 10° C. for 1 hr to give a yellow solution. LCMS showedreactant was completely consumed and the desired MS. The reactionmixture was diluted with H₂O (20 mL) and extracted with EtOAc (30 mL×2).The combined organic layer was dried over Na₂SO₄ and concentrated invacuum to give a residue as yellow oil. The crude was purified byPrep-HPLC (NH₃). The afford flows was concentrated in vacuum to removemost of CH₃CN and lyophilized to give the title compound (52.53 mg,0.1600 mmol, 48.99% yield) as white solid.

LC-MS Method1: 329.2 [M+H⁺] ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.69 (d,J=1.6 Hz, 1H), 7.48 (d, J=1.2 Hz, 1H), 4.39-4.22 (m, 3H), 3.89-3.84 (m,2H), 2.98 (s, 2H), 2.20 (m, 1H), 2.06 (m, 1H), 1.50 (d, J=6.4 Hz, 6H),1.22 (s, 3H), 1.16-1.07 (m, 2H), 0.74-0.67 (m, 2H) Example 85(1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

(1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 1-cyclopropylimidazole-4-carboxylic acid (25.12 mg,0.1700 mmol) in DMF (1 mL) were added HATU (71.11 mg, 0.1900 mmol) andDIPEA (100.16 mg, 0.7800 mmol). The mixture was stirred at 25° C. for0.5 h. Then6-[(1R,5S,6r)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-eneTFA salt (50 mg, 0.1600 mmol) was added to the mixture. The mixture wasstirred at 25° C. for 12 h to give brown solution. LCMS showed thedesire MS as a major peak. The reaction mixture was concentrateddirectly. The residue was purified by prep-HPLC (NH₃) to give the titlecompound (11.52 mg, 0.0353 mmol, 20% yield) as brown solid.

LC-MS Method2 1.763 min, MS (m/z) 327.2 [M+H⁺]¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.66 (1H, d, J=1.25 Hz), 7.51 (1H,d, J=1.25 Hz), 4.18-4.35 (2H, m), 3.82-3.92 (2H, m), 3.37 (1H, tt,J=7.31, 3.73 Hz), 2.99 (2H, s), 2.20 (1H, dd, J=8.16, 5.14 Hz),2.01-2.12 (1H, m), 1.19-1.24 (3H, m), 1.09-1.17 (2H, m), 0.96-1.08 (4H,m), 0.67-0.76 (2H, m)

Example 86[1-(1-methylcyclopropyl)-1H-imidazol-4-yl][(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone[1-(1-methylcyclopropyl)-1H-imidazol-4-yl][(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 1-(1-methylcyclopropyl) imidazole-4-carboxylic acid(37.98 mg, 0.2300 mmol) in DMF (2 mL) were added HATU (104.22 mg, 0.2700mmol) and DIPEA (0.19 mL, 1.14 mmol). The mixture was stirred at 25° C.for 30 min. Then6-[(1R,5S,6r)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-eneTFA salt (70 mg, 0.2300 mmol) was added to the mixture. The mixture wasstirred at 25° C. for 3 h to give brown solution. The reaction mixturewas concentrated directly. The residue was purified by prep-HPLC (NH₃)to give the title compound (15.64 mg, 0.0459 mmol, 20.102% yield) asbrown solid.

LC-MS Method1: 341.3 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.65 (2H, br d, J=6.25 Hz)4.10-4.26 (2H, m) 3.77-3.92 (2H, m) 3.00 (2H, s) 2.20-2.29 (1H, m)2.07-2.15 (1H, m) 1.59 (3H, s) 1.17-1.23 (3H, m) 1.08-1.17 (4H, m)0.93-1.00 (2H, m) 0.69-0.76 (2H, m)

Example 87(1R,5S,6r)-N-tert-butyl-6-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide(1R,5S,6r)-6-methyl-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid

To a solution of tert-butyl(1R,5S,6r)-6-formyl-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.44 mmol) in 1-BuOH (1.7 mL, 0.44 mmol), THF (1.7 mL), and H₂O(0.60 mL) were added 2-methylbut-2-ene (0.94 mL, 8.88 mmol), NaClO₂(160.58 mg, 1.78 mmol) and NaH₂PO₄ (490.02 mg, 3.55 mmol). The resultingmixture was stirred at 20 to 25° C. for 16 h. TLC (PE:EtOAc=2:1) showedthe reaction was completed (Rf=0.5). The reaction mixture was pouredinto H₂O (10 mL) and extracted with EtOAc (10 mL×4). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford the title compound (167 mg, 0.6921 mmol,155.93% yield) as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=3.66-3.56 (m, 2H), 3.47-3.34 (m, 2H),2.26-2.18 (m, 2H), 1.47-1.42 (m, 9H), 1.17 (s, 3H) tert-butyl(1R,5S,6r)-6-methyl-6-[(tert-butyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of(1R,5S,6r)-6-methyl-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (100 mg, 0.41 mmol) in Pyridine (1 mL) was added EDCI (119.18 mg,0.62 mmol). The mixture was stirred at 20 to 25° C. for 0.5 h. Then2-methylpropan-2-amine (0.04 mL, 0.41 mmol) was added. The resultingmixture was stirred at 20 to 25° C. for 16 h. TLC (PE:EA=1:1) showed thereaction was completed. The crude product was purified by flash column(PE to 30% EtOAc in PE) to afford the title compound (50 mg, 0.1687mmol, 40.7% yield) as a brown solid.

1H NMR (400 MHz, CHLOROFORM-d) δ=3.67-3.55 (m, 2H), 3.36 (d, J=11.9 Hz,1H), 3.28 (d, J=11.8 Hz, 1H), 2.15-2.04 (m, 2H), 1.48-1.42 (m, 9H),1.48-1.42 (m, 1H), 1.39-1.30 (m, 9H), 1.13 (s, 3H)(1R,5S,6r)-6-methyl-N-(tert-butyl)-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt

A solution of tert-butyl(1R,5S,6r)-6-methyl-6-[(tert-butyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(50 mg, 0.17 mmol) in DCM (1 mL) and 2,2,2-trifluoroacetic acid (0.1 mL,1.31 mmol) was stirred at 20 to 25° C. for 1 h. TLC (PE:EtOAc=1:1)showed the reaction was completed (Rf=0.3). The reaction mixture wasconcentrated by purging with N₂ to afford the title compound (30 mg,0.1528 mmol, 90.604% yield) as a brown oil.

(1R,5S,6r)-N-tert-butyl-6-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a solution of 1-isopropylimidazole-4-carboxylic acid (23.56 mg, 0.15mmol) in DMF (0.50 mL) were added HATU (75.96 mg, 0.20 mmol) and Et₃N(0.06 mL, 0.46 mmol). The mixture was stirred at 20 to 25° C. for 0.5 h.Then(1R,5S,6r)-6-methyl-N-(tert-butyl)-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt (30 mg, 0.15 mmol) was added to the mixture. The resultingmixture was stirred at 20 to 25° C. for 2 h. LCMS showed the desired MS(as a major peak). The residue was purified by prep-HPLC (NH₃). Theafforded flows were combined, concentrated to remove most of CH₃CN andlyophilized to afford the title compound (10.28 mg, 0.0309 mmol, 20.233%yield) as an off-white solid.

LC-MS Method1: 333.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.69 (s, 1H), 7.48 (s, 1H), 5.58 (s,1H), 4.36 (td, J=6.7, 13.4 Hz, 1H), 4.24 (d, J=2.3 Hz, 2H), 3.94-3.85(m, 1H), 3.74 (d, J=13.3 Hz, 1H), 2.30-2.25 (m, 1H), 2.12 (dd, J=5.4,8.2 Hz, 1H), 1.51 (d, J=6.8 Hz, 6H), 1.36 (s, 9H), 1.15 (s, 3H)

Example 88[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (21.34 mg,0.1400 mmol) in DMF (1 mL) were added HATU (63.13 mg, 0.1700 mmol),DIPEA (0.08 mL, 0.4800 mmol) and(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (30 mg, 0.1400 mmol). The mixture was stirred at 25° C.for 12 h to give brown solution. TLC (PE:EtOAc=1:3) showed a new spot.The reaction mixture was poured into H₂O (10 mL) and extracted withEtOAc (20 mL×3). The combined organic layers were washed with brine (30mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by prep-TLC (PE:EtOAc=1:3) andlyophilized to give the title compound (18.42 mg, 0.0570 mmol, 41.171%yield) as white powder.

LC-MS Method1 0.781 min, MS (m/z) 317.0 [M+H⁺]¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.41 (s, 1H), 4.13-4.28 (m, 2H),3.95 (br dd, J=11.17, 4.14 Hz, 1H), 3.69 (br dd, J=12.92, 4.39 Hz, 1H),3.06 (quin, J=6.84 Hz, 1H), 2.66 (s, 2H), 2.15 (br dd, J=7.40, 3.39 Hz,1H), 2.02-2.08 (m, 1H), 1.47 (t, J=3.26 Hz, 1H), 1.38 (s, 6H), 1.27-1.31(m, 6H)

Example 89(5-sec-butyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanoneethyl 5-methyl-2,4-dioxoheptanoate

To a solution of 3-methylpentan-2-one (0.61 mL, 4.99 mmol) and diethyloxalate (0.81 mL, 5.99 mmol) in THF (20 mL) was added NaH (239.62 mg,5.99 mmol) at 0° C. The reaction was allowed to warm to 20° C. andstirred for further 6 h to give pale brown solution. The reaction wascooled to 0° C., treated with H₂O (30 mL), acidified with 2M HCl to pH=6and extracted with EA (20 mL×2). The combined organic layer was driedover Na₂SO₄ and concentrated in vacuum to give the title compound (1000mg, 4.9943 mmol) as pale brown liquid.

¹H NMR (400 MHz, CHLOROFORM-d) δ=14.60 (brs, 1H), 6.40 (s, 1H), 4.26 (q,J=6.8 Hz, 2H), 2.55-2.40 (m, 1H), 1.60-1.50 (m, 1H), 1.50-1.35 (m, 1H),1.38 (t, J=6.8 Hz, 3H), 1.10 (d, J=7.4 Hz, 3H), 0.82 (t, J=6.8 Hz, 3H).

ethyl 5-sec-butyl-1H-pyrazole-3-carboxylate

To a solution of ethyl 5-methyl-2,4-dioxoheptanoate (1000 mg, 4.99 mmol)in EtOH (20 mL) was added hydrazine hydrate (275.01 mg, 5.49 mmol) at20° C. After stirred for 20 min, the reaction was heated at 60° C. forfurther 4 h to give yellow mixture. The mixture was concentrated invacuum to give crude oil. The oil was diluted with EA (40 mL), washedwith H₂O (30 mL×2) and brine (30 mL), then, dried over Na₂SO₄ andconcentrated in vacuum to give the title compound (950 mg, 4.8408 mmol,96.927% yield) as pale yellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=6.55 (s, 1H), 4.31 (q, J=6.8 Hz, 2H),2.80-2.35 (m, 1H), 1.70-1.50 (m, 2H), 1.37 (t, J=6.8 Hz, 3H), 1.31 (d,J=7.4 hz, 3H), 0.82 (t, J=6.8 Hz, 3H).5-sec-butyl-1H-pyrazole-3-carboxylic acid

To a solution of ethyl 5-sec-butyl-1H-pyrazole-3-carboxylate (950 mg,4.84 mmol) in MeOH (15 mL) and H₂O (5 mL) was added LiOH.H₂O (0.42 mL,7.26 mmol). The reaction was stirred at 20° C. for 12 h to give yellowmixture. The mixture was concentrated to remove MeOH. The residue wasdiluted with H₂O (5 mL) and washed with DCM (5 mL×2). The aqueous layerwas cooled to 0° C. and acidified with 2M HCl to pH=6. The precipitatewas collected and concentrated in vacuum to give the title compound (420mg, 2.4972 mmol, 51.586% yield) as a white solid.

(5-sec-butyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 5-sec-butyl-1H-pyrazole-3-carboxylic acid (50 mg,0.3000 mmol) in DMF (1.5 mL) were added HATU (125.02 mg, 0.3300 mmol),(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (70.87 mg, 0.3300 mmol) and Et₃N (0.1 mL, 0.7400 mmol). Thereaction was stirred at 20° C. for 12 h to give pale yellow mixture. Themixture was concentrated in vacuum and purified by prep-HPLC (HCl). Theafforded eluent was concentrated and lyophilized to give the titlecompound (10.38 mg, 0.0314 mmol, 10.567% yield) as pale yellow solid.

LC-MS Method1: 331.0 [M+H⁺]

¹H NMR (400 MHz, DMSO-d₆) δ=6.51-6.28 (m, 1H), 4.30 (br d, J=11.9 Hz,1H), 3.94 (d, J=12.3 Hz, 1H), 3.83 (dd, J=4.2, 11.8 Hz, 1H), 2.80-2.71(m, 1H), 2.65 (s, 2H), 2.08 (td, J=3.7, 7.4 Hz, 1H), 2.00 (td, J=3.8,7.3 Hz, 1H), 1.65-1.51 (m, 2H), 1.47-1.41 (m, 1H), 1.25 (s, 611), 1.20(d, J=6.9 Hz, 3H), 0.80 (t, J=7.4 Hz, 3H)

Example 90[5-(1-cyclopropylethyl)-1H-pyrazol-3-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonemethyl5-acetyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylate

A solution of methyl5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylate(1500 mg, 4.47 mmol, Tetrahedron 2015, 71(39), 7250),tributyl(1-ethoxyvinyl)stannane (1938.94 mg, 5.37 mmol) and PdCl₂(dppf)(163.68 mg, 0.2200 mmol) in 1,4-Dioxane (25 mL) was heated to 9° C. for16 hr give a yellow solution. IM HCl aq. (3 mL) was added to be stirredfor 10 min. Then the reaction was diluted with H₂O (20 mL) and it wasextracted with EtOAc (30 mL×2). The combined organic layer was driedover Na₂SO₄ and concentrated in vacuum to give a yellow oil. The crudewas purified by silica gel chromatography (PE/EA=10/1 to 3/1) to givethe title compound (580 mg, 1.9436 mmol, 43.443% yield) as white solid.

LC-MS Method1 0.972 min, MS (m/z) 299.0 (M+H⁺).

methyl5-{(1E)-N-[(4-methylphenyl)sulfonyl]ethanehydrazonoyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylate

A 100 mL round-bottom flask was charged with methyl5-acetyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylate(810 mg, 2.71 mmol), 4-methylbenzenesulfonohydrazide (505.5 mg, 2.71mmol), 4-methylbenzenesulfonic acid (0.02 mL, 0.1400 mmol) and MeOH (10mL). The reaction was stirred at 40° C. for 16 hr to give a yellowsolution. The reaction mixture was evaporated in vacuum to give thetitle compound (1250 mg, 2.6788 mmol, 98.688% yield) as yellow oil. Itused directly in the next step.

LC-MS Method1 1.012 min, MS (m/z) 467.1 (M+H⁺).

methyl5-(1-cyclopropylethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylate

A round-bottom flask was charged with methyl5-{(1E)-N-[(4-methylphenyl)sulfonyl]ethanehydrazonoyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylate(500 mg, 1.07 mmol), cyclopropylboronic acid (138.06 mg, 1.61 mmol),K₂CO₃ (222.14 mg, 1.61 mmol) and 1,4-Dioxane (10 mL). The reaction washeated to 110° C. for 2 hr to give a white suspension. TLC (PE/EA=10/1,Rf=0.7) showed a new spot. The reaction mixture was filtered through apad of celite and the filtrate was concentrated in vacuum to give acolorless oil. The crude was purified by silica gel chromatography(PE/EA=10/1 to 3/1) to give the title compound (230 mg, 0.6904 mmol,64.43% yield) as colorless oil.

LC-MS Method1 1.105 min, MS (m/z) 325.2 (M+H⁺).

methyl 5-(1-cyclopropylethyl)-1H-pyrazole-3-carboxylate

A round-bottom flask was charged with methyl5-(1-cyclopropylethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylate(230 mg, 0.7100 mmol), 2,2,2-trifluoroacetic acid (0.05 mL, 0.7100 mmol)and DCM (10 mL). The reaction mixture was stirred at 20° C. for 2 hr togive a yellow solution. The reaction mixture was evaporated in vacuum togive the title compound (130 mg, 0.6693 mmol, 94.428% yield) as yellowoil.

LC-MS Method1 0.785 min, MS (m/z) 195.2 (M+H⁺).

5-(1-cyclopropylethyl)-1H-pyrazole-3-carboxylic acid A 100 mLround-bottom flask was charged with methyl5-(1-cyclopropylethyl)-1H-pyrazole-3-carboxylate (130 mg, 0.6700 mmol),hydroxylithium hydrate (84.25 mg, 2.01 mmol), H₂O (1.3 mL), THF (1.3 mL)and MeOH (1.3 mL). The reaction mixture was stirred under N₂ atmospherefor 3 hr to give a yellow solution. H₂O (30 mL) was added and pH valuewas adjusted to 3 with 1M HCl. It was extracted with EtOAc (30 mL×2).The combined organic layer was dried over Na₂SO₄ and concentrated invacuum to give the title compound (120 mg, 0.6659 mmol, 99.495% yield)as yellow oil.

LC-MS Method1 0.732 min, MS (m/z) 181.2 (M+H⁺).

[5-(1-cyclopropylethyl-1H-pyrazol-3-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 5-(1-cyclopropylethyl)-1H-pyrazole-3-carboxylic acid(80 mg, 0.4400 mmol) in DMF (2 mL) were added HATU (203.67 mg, 0.5300mmol) and N-ethyl-N-isopropylpropan-2-amine (0.46 mL, 2.66 mmol). Afterstirred for 30 min,(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (278.26 mg, 0.5300 mmol) was added. The reaction mixture wasstirred for 16 hr to give a yellow solution. H₂O (30 mL) was added andit was extracted with EtOAc (30 mL×2). The combined organic layer wasdried over Na₂SO₄ and concentrated in vacuum to give a yellow oil. Thecrude was purified by Prep-TLC (DCM/EA=3/1) and lyophilized to give thetitle compound (16.86 mg, 0.0459 mmol, 10.346% yield) as white solid.

LC-MS Method1: 343.0 [M+H⁺]

¹H NMR (400 MHz, CDCl₃) δ ppm 6.55 (s, 1H), 3.33 (d, J=11.2 Hz, 1H),3.20 (d, J=11.2 Hz, 1H), 3.95-3.85 (m, 1H), 3.70-3.60 (m, 1H), 2.65 (s,2H), 2.20-2.10 (m, 2H), 2.05-2.00 (m, 1H), 1.45-1.40 (m, 1H), 1.38 (s,9H), 0.95-0.85 (m, 1H), 0.58 (d, J=7.6 Hz, 2H), 0.30-0.20 (m, 2H).

Example 91[5-(1-cyclobutylethyl)-1H-pyrazol-3-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanoneN′-[(1E)-1-cyclobutylethylidene]-4-methylbenzenesulfonohydrazide

A solution of 1-cyclobutylethanone (350 mg, 3.57 mmol) and TsNHNH₂(664.16 mg, 3.57 mmol) in MeOH (7 mL) was stirred at 25° C. for 4 hr.The solvent was concentrated by reduce pressure to give the crudeproduct. The crude product was triturated by (PE:EtOAc=10:1, 10 mL) toafford the title compound (820 mg, 3.0785 mmol, 86.322% yield) as awhite solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.86 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz,2H), 3.10-2.90 (m, 1H), 2.43 (s, 3H), 2.10-2.00 (m, 6H), 1.68 (s, 3H).

3-(1-cyclobutylvinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylicacid

To a solution of methyl3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylate(300 mg, 0.89 mmol),N′-[(1E)-1-cyclobutylethylidene]-4-methylbenzenesulfonohydrazide (238.34mg, 0.89 mmol) and t-BuOLi (214.89 mg, 2.68 mmol) in 1,4-Dioxane (5 mL)were added XPhos (42.66 mg, 0.09 mmol) and Pd₂(dba)₃ (40.97 mg, 0.04mmol) at 25° C. under N₂. The mixture was stirred at 110° C. for 12 hr.The mixture was poured into H₂O (10 mL), and then adjusted pH to 4 to 5by 1M HCl and extracted by EtOAc (10 mL×3). The organic phase was washedby brine (15 mL), then dried over anhydrous Na₂SO₄ and the solvent wasremoved. The residue was purified by SiO₂ column chromatography(PE:EtOAc=1:0-5:1, 0.5% FA) to afford the title compound (200 mg, 0.6202mmol, 69.313% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.23 (s, 1H), 7.05 (s, 1H), 5.81 (s, 2H),5.81 (s, 1H), 3.70-3.60 (m, 2H), 3.00-2.80 (m, 2H), 2.30-1.90 (m, 6H),1.00-0.90 (m, 2H), 0.03 (s, 9 h).

3-(1-cyclobutylethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylicacid

To a solution of3-(1-cyclobutylvinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylicacid (200 mg, 0.62 mmol) in MeOH (4 mL) was added Pd/C (100 mg) underN₂. The mixture was stirred at 25° C. under H2 (15 psi) for 12 hr. Themixture was filtered through Celite and the filtrate was concentrated togive the title compound (200 mg, 0.6164 mmol, 99377% yield) as acolorless oil. The crude was used directly for next step.

¹H NMR (400 MHz, CDCl₃) δ ppm 6.77 (s, 2H), 5.80-5.70 (m, 2H), 3.60-3.50(m, 2H), 2.80-2.70 (m, 1H), 2.45-2.30 (m, 1H), 2.20-2.00 (m, 1H),1.80-1.60 (m, 5H), 1.43 (d, J=6.8 Hz, 3H), 0.80-0.70 (m, 2H), 0.06 (s,9H).

methyl 3-(l-cyclobutylethyl)-1H-pyrazole-5-carboxylate

To a solution of3-(1-cyclobutylethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylicacid (100 mg, 0.310 mmol) in MeOH (4 mL) was added TFA (175.69 mg, 1.54mmol) at 25° C. The mixture was stirred at 60° C. for 12 hr. The mixturewas stirred at 70° C. for 6 hr. The mixture was concentrated to give thecrude title compound (100 mg, 0.2881 mmol, 93.486% yield) as yellow oil.The crude was used directly for next step.

LC-MS Method1: 0.818 min, MS (m/z) 209.1 (M+H⁺).

3-(1-cyclobutylethyl)-1H-pyrazole-5-carboxylic acid

To a solution of methyl 3-(1-cyclobutylethyl)-1H-pyrazole-5-carboxylate(100 mg, 0.480 mmol) in THE (1 mL) and H₂O (2 mL) was added LiOH.H₂O(80.59 mg, 1.92 mmol). The mixture was stirred at 20° C. for 2 hr. Themixture was diluted with H₂O (10 mL), adjusted pH to 4 to 5 by IM HCland extracted by EA (10 mL×3). The combined organic layer was dried overNa₂SO₄ and the solvent was removed to give the title compound (80 mg,0.4119 mmol, 85.779% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.66 (s, 1H), 2.90-2.70 (m, 1H), 2.50-2.30(m, 1H), 2.00-1.50 (m, 6H), 1.25 (d, J=6.8 Hz, 3H).

[5-(1-cyclobutylethyl)-1H-pyrazol-3-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 3-(1-cyclobutylethyl)-1H-pyrazole-5-carboxylic acid(120 mg, 0.62 mmol) and EDCI (130 mg, 0.68 mmol) in Pyridine (5 mL) wasadded(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (120 mg, 0.67 mmol). The mixture was stirred at 20° C. for 2 h.The reaction mixture was concentrated to give a residue. The residue waspurified by Prep-HPLC (NH₃) to give the title compound (10 mg, 0.028mmol) as a white solid.

LC-MS Method1: 357.1 [M+H⁺]

¹H NMR (400 MHz, CDCl₃) δ ppm 6.44 (s, 1H) 4.32 (d, J=11.6 Hz, 1H) 4.20(d, J=12.6 Hz, 1H) 3.92 (dd, J=11.4, 4.3 Hz, 1H) 3.65 (dd, J=12.6, 4.3Hz, 1H) 3.60-3.70 (m, 1H) 2.82-2.78 (m, 1H) 2.66 (s, 2H) 2.35-2.46 (m,1H) 1.73-2.17 (m, 8H) 1.44 (t, J=3.4 Hz, 1H) 1.38 (s, 6H) 1.18 (d, J=7.0Hz, 3H)

Example 92(5-cyclopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-cyclopropvl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a stirred solution of 5-cyclopropyl-1H-pyrazole-3-carboxylic acid(23.0 mg, 0.151 mmol) and HATU (57.5 mg, 0.151 mmol) in THF (0.76 mL)was added DIPEA (0.13 mL, 0.756 mmol). After stirred at 50° C. for 30min,(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (36.0 mg, 0.166 mmol) was added and the reaction wasstirred at 50° C. for 1 hr to give a yellow solution. H₂O was added andit was extracted with DCM. The combined organic layer was dried overNa₂SO₄ and concentrated in vacuum to give a yellow oil. The crude waspurified by silica gel chromatography (EtOAc/DCM=99/1 to 80/20) to givethe title compound (14.7 mg, 0.047 mmol, 47.5% yield) as a beige powder.

LC-MS Method1: 315.0[M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=6.30 (s, 1H), 4.23 (d. J=11.7 Hz, 1H),4.18 (d. J=12.9 Hz, 1H), 3.88 (dd, J=11.1, 4.2 Hz, 1H), 3.64 (dd,J=12.9, 4.5 Hz, 1H), 2.65 (s, 2H), 2.15-2.01 (m, 2H), 1.92-1.87 (m, 1H),1.42 (t, J=3.0 Hz, 1H), 1.37 (s, 6H), 0.99-0.94 (m, 2H), 0.77-0.72 (m,2H)

Example 93(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of(1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (50 mg, 0.3000 mmol) in DMF (0.50 mL) were added DIPEA(0.2 mL, 1.2 mmol), 5-isopropyl-1H-pyrazole-3-carboxylic acid (46.38 mg,0.3000 mmol) and HATU (148.6 mg, 0.3900 mmol). The resulting mixture wasstirred at 20° C. for 16 hr to give brown mixture. TLC (PE/EA=O/1)showed new spots and the reactant was consumed completed. The reactionmixture was diluted with H₂O (5 mL), extracted with EtOAc (5 mL×2), andthen washed with H₂O (5 mL) and brine (5 mL×2). The combined organiclayers were separated, then dried over Na₂SO₄ and concentrated in vacuumto give crude product. The crude product was purified by prep-HPLC (NH₃)to give the title compound (2.11 mg, 0.0070 mmol, 2.3198% yield) aswhite solid.

¹H NMR (400 MHz, CDCl₃) δ=6.40 (s, 1H), 4.63-4.56 (m, 1H), 4.23 (br d,J=11.3 Hz, 1H), 4.13 (d, J=12.8 Hz, 1H), 3.84 (dd, J=4.3, 11.5 Hz, 1H),3.58 (dd, J=4.0, 12.8 Hz, 1H), 2.98-2.88 (m, 2H), 2.47-2.38 (m, 1H),2.08 (br d, J=3.5 Hz, 1H), 1.98 (br s, 1H), 1.28-1.20 (m, 12H)

Example 94{(1R,5S,6r)-6-[5,5-dimethyl-4-(3-methylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanonetert-butyl(1R,5S,6r)-6-[5,5-dimethyl-4-(3-methylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(220 mg, 0.8400 mmol) and 1-methyl-3-(2-methyl-1-propen-1-yl)benzene(246.78 mg, 1.69 mmol) in DCM (5 mL) was added triethylamine (0.23 mL,1.69 mmol). The reaction mixture was stirred at 10° C. for 16 hr to givea yellow solution. TLC (PE/EA=3/1 Rf=0.7) showed a new spot wasdetected. H₂O (15 mL) was added and it was extracted with EtOAc (15mL×2). The combined organic layer was dried over Na₂SO₄ and concentratedin vacuum to give a yellow oil. The crude was purified by silica gelchromatography (PE/EA=1/0 to 3/1) to give the title compound (120 mg,0.3239 mmol, 38.385% yield) as yellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.40-7.30 (m, 1H), 7.20-7.10 (m, 1H),6.80-6.70 (m, 2H), 3.62 (s, 1H), 3.55-3.35 (m, 2H), 3.35-3.20 (m, 2H),2.29 (s, 3H), 1.70-1.60 (m, 1H), 1.32 (s, 9H), 1.108 (s, 3H), 0.86 (s,3H), 0.60-0.50 (m, 2H). 30 [0572]

(1R,5S,6r)-6-[5,5-dimethyl-4-(3-methylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexaneTFA salt

A solution of tert-butyl(1R,5S,6r)-6-[5,5-dimethyl-4-(3-methylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(120 mg, 0.3200 mmol) in HCl/dioxane (2 mL, 0.3200 mmol) was stirred at10° C. for 3 hr to give a yellow solution. It was evaporated in vacuumto give the title compound (110 mg, 0.3585 mmol, 110.69% yield) asyellow oil

{(1R,5S,6r)-6-[5,5-dimethyl-4-(3-methylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (12 mg,0.0800 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.04 mL, 0.2300mmol) in DMF (1 mL) was added HATU (32.73 mg, 0.0900 mmol). Afterstirred for 30 min,(1R,5S,6r)-6-[5,5-dimethyl-4-(3-methylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexaneTFA salt (20.3 mg, 0.0700 mmol) was added to be stirred for 16 hr togive a yellow solution. H₂O (30 mL) was added and it was extracted withEtOAc (30 mL×2). The combined organic layer was dried over Na₂SO₄ andconcentrated in vacuum to give a yellow oil. The crude was purified byPrep-HPLC (FA). The afford flows were concentrated in vacuum to removemost of CH₃CN and lyophilized to give the title compound (1.25 mg,0.0031 mmol, 3.9505% yield) as white solid.

LC-MS Method1: 407.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.22 (d, J=7.50 Hz, 1H), 7.11 (br d,J=7.38 Hz, 1H), 6.81-6.87 (m, 2H), 6.40 (s, 1H), 4.10-4.20 (m, 1H),3.98-4.08 (m, 1H), 3.84 (ddd, J=4.44, 11.29, 19.54 Hz, 1H), 3.70 (d,J=3.00 Hz, 1H), 3.57 (td, J=4.60, 12.57 Hz, 1H), 2.99 (td, J=6.86, 13.91Hz, 1H), 2.35 (s, 3H), 2.29 (td, J=3.86, 7.41 Hz, 1H), 2.13 (td, J=3.77,7.35 Hz, 1H), 2.01 (td, J=3.81, 7.13 Hz, 1H), 1.89 (td, J=3.85, 7.32 Hz,1H), 1.39 (s, 3H), 1.27 (d, J=7.00 Hz, 6H), 0.94 (s, 3H)

Example 95(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

A 100 ml round-bottom flask was charged with5-isopropyl-1H-pyrazole-3-carboxylic acid (125 mg, 0.8100 mmol), HATU(371.96 mg, 0.9700 mmol), DMF (4 mL), N-ethyl-N-isopropylpropan-2-amine(0.42 mL, 2.43 mmol) and DMF (4 mL). After stirred for 30 mi,6-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-enehydrochloride (236.95 mg, 0.8100 mmol) was added. The reaction mixturewas stirred at 10° C. for 16 hr to give a yellow solution. H₂O (20 mL)was added and it was extracted with EtOAc (30 mL×2). The combinedorganic layer was dried over Na₂SO₄ and concentrated in vacuum to give ayellow oil. The crude was purified by Prep-HPLC (FA). The afford flowswere concentrated in vacuum to remove most of CH₃CN and lyophilized togive the title compound (36.35 mg, 0.1156 mmol, 14.261% yield) as whitesolid.

LC-MS Method1: 315.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ 6.48 (s, 1H), 4.29-4.34 (m, 1H), 4.21(d, J=12.55 Hz, 1H), 3.93 (dd, J=4.52, 11.54 Hz, 1H), 3.66 (dd, J=4.39,12.67 Hz, 1H), 3.00-3.06 (m, 1H), 2.98 (s, 2H), 2.19 (td, J=3.58, 7.40Hz, 1H), 2.08 (td, J=3.89, 7.28 Hz, 1H), 1.50 (t, J=3.39 Hz, 1H), 1.30(d, J=7.03 Hz, 6H), 1.09-1.14 (m, 2H), 0.65-0.74 (m, 2H)

Example 96(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[(1S,5S)-2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[(1S,5S)-2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone

12 mg of(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(Example 97) was sent for SFC chiral separation to afford the titlecompound (4.95 mg)

LC-MS Method1: 301.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.27 (1H, br s), 6.41 (1H, s),4.79 (1H, td, J=5.33, 2.13 Hz), 4.27 (1H, br d, J=11.04 Hz), 4.16 (1H,dd, J=12.67, 1.38 Hz), 3.82-3.93 (1H, m), 3.60 (1H, br dd, J=12.55, 5.02Hz), 2.95 (1H, spt, J=6.94 Hz), 2.25-2.36 (1H, m), 2.13-2.21 (1H, m),2.08 (1H, br s), 1.96-2.21 (1H, m), 1.96-2.03 (1H, m), 1.57 (1H, t,J=3.39 Hz), 1.23 (6H, d, J=7.03 Hz), 0.81 (1H, dt, J=9.29, 5.52 Hz),0.24 (1H, br d, J=2.51 Hz)

Example 97(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (25.82 mg,0.1700 mmol) in DMF (2.0833 mL) were added HATU (75.67 mg, 0.2000 mmol)and DIPEA (0.08 mL, 0.4600 mmol). The mixture was stirred at 25° C. for30 min. Then4-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-2-oxa-3-azabicyclo[3.1.0]hex-3-ene(25 mg, 0.1500 mmol) was added to the mixture. The mixture was stirredat 25° C. for 3 h to give brown solution. The reaction mixture wasconcentrated directly. The residue was purified by prep-HPLC (NH₃) togive the title compound (21.39 mg, 0.0712 mmol, 46.774% yield) as whitesolid.

LC-MS Method1: 301.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.27 (1H, br s), 6.41 (1H, s),4.79 (1H, td, J=5.33, 2.13 Hz), 4.27 (1H, br d, J=11.04 Hz), 4.16 (1H,dd, J=12.67, 1.38 Hz), 3.82-3.93 (1H, m), 3.60 (1H, br dd, J=12.55, 5.02Hz), 2.95 (1H, spt, J=6.94 Hz), 2.25-2.36 (1H, m), 2.13-2.21 (1H, m),2.08 (1H, br s), 1.96-2.21 (1H, m), 1.96-2.03 (1H, m), 1.57 (1H, t,J=3.39 Hz), 1.23 (6H, d, J=7.03 Hz), 0.81 (1H, dt, J=9.29, 5.52 Hz),0.24 (1H, br d, J=2.51 Hz)

Example 98[(1R,5S,6r)-6-(4-isobutyl-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone[(1R,5S,6r)-6-(4-isobutyl-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of(1R,5S,6r)-6-(4-isobutyl-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (300 mg, 1.27 mmol) and DIPEA (1.05 mL, 6.35 mmol) in DMF(8.5 mL) were added HATU (578 mg, 1.52 mmol) and5-isopropyl-1H-pyrazole-3-carboxylic acid (195 mg, 1.27 mmol), and themixture was stirred at 20° C. for 12 hr. LCMS showed the desired masswas detected. The reaction mixture was poured into H₂O (30 mL) andextracted by EtOAc (20 mL×3). The organic phase was washed by brine (50mL), dried over anhydrous Na₂SO₄ and concentrated to give a residue. Theresidue was purified by Prep-HPLC (NH₃) to afford the title compound (12mg, 0.03 mmol, 2.53% yield) as a white solid.

LC-MS Method1: 373.2 [M+H⁺]

¹H NMR (400 MHz, METHANOL-d₄) δ ppm 0.93-1.01 (m, 6H) 1.19 (d, J=1.6 Hz,3H) 1.30 (d, J=6.9 Hz, 9H) 1.35 (d, J=2.1 Hz, 3H) 1.41-1.49 (m, 2H)1.69-1.79 (m, 1H) 1.98-2.25 (m, 3H) 2.95 (br t, J=7.2 Hz, 1H) 2.99-3.08(m, 1H) 3.57-3.69 (m, 1H) 3.93 (br d, J=12.0 Hz, 1H) 4.01-4.15 (m, 1H)4.37 (br dd, J=11.9, 5.4 Hz, 1H) 6.45 (s, 1H)

Example 99(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of 5-isopropyl-1H-pyrazole-3-carboxylic acid (39.68 mg,0.2600 mmol) in DMF (0.4639 mL) were added HATU (127.91 mg, 0.3300 mmol)and DIPEA (0.21 mL, 1.29 mmol). The mixture was heated at 50° C. for 30min.(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (50 mg, 0.2600 mmol) was added. The resulting mixture wasstirred at 20° C. for 4 hr. The reaction mixture was diluted with H₂O(10 mL), extracted with EtOAc (10 mL×2), and then washed with brine (10mL). The combined organic layers were separated, then dried over Na₂SO₄and concentrated in vacuum to give crude oil. The crude oil was purifiedby prep-HPLC (NH₃) and lyophilized to give the title compound (4.91 mg,0.0149 mmol, 5.7737% yield) as white solid.

¹H NMR (400 MHz, MeOD) δ=6.47 (s, 1H), 4.39 (br d, J=12.0 Hz, 1H), 4.12(dd, J=5.4, 12.7 Hz, 1H), 3.95 (br d, J=12.5 Hz, 1H), 3.64 (br d, J=12.8Hz, 1H), 3.16-3.01 (m, 1H), 2.92 (q, J=7.2 Hz, 1H), 2.25-2.00 (m, 2H),1.37 (br s, 1H), 1.36-1.27 (m, 12H), 1.22 (s, 3H)

Example 100[(1R,5S,6r)-6-(5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone[(1R,5S,6r)-6-(5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

To a mixture of 5-isopropyl-1H-pyrazole-3-carboxylic acid (23.81 mg,0.1500 mmol) in DMF (0.2783 mL) were added HATU (76.75 mg, 0.2000 mmol),DIPEA (0.13 mL, 0.7700 mmol) and(1R,5S,6r)-6-(5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (30 mg, 0.1500 mmol). The resulting mixture was stirred at 20°C. for 4 hr. The reaction mixture was diluted with H₂O (5 mL), extractedwith EtOAc (5 mL×2), and then washed with brine (8 mL). The combinedorganic layers were separated, then dried over Na₂SO₄ and concentratedin vacuum to give crude oil. The crude oil was purified by prep-HPLC(NH₃) and lyophilized to give the title compound (1.82 mg, 0.0055 mmol,3.5669% yield) as white solid.

¹H NMR (400 MHz, MeOD) δ=6.47 (br s, 1H), 4.37 (br s, 1H), 4.12 (d,J=12.8 Hz, 1H), 3.95 (dd, J=3.8, 12.3 Hz, 1H), 3.64 (dd, J=4.4, 12.4 Hz,1H), 3.08-3.01 (m, 1H), 2.87-2.74 (m, 1H), 2.73-2.59 (m, 1H), 2.19-2.04(m, 2H), 1.68-1.60 (m, 2H), 1.52-1.48 (m, 1H), 1.32-1.30 (m, 9H), 0.94(t, J=7.5 Hz, 3H)

Example 101(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (49.12 mg,0.3200 mmol) in DMF (2.393 mL) were added HATU (91.62 mg, 0.4800 mmol)and DIPEA (0.16 mL, 0.9600 mmol). The reaction mixture was stirred at15° C. for 30 min. Then(1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (67 mg, 0.3200 mmol) was added to the reaction. The reactionmixture was stirred at 15° C. for 0.5 hr to give a yellow mixture. LCMSshowed the desired MS. The reaction mixture was purified by prep-HPLC(NH₃) to give the title compound (43.85 mg, 0.1266 mmol, 39.725% yield)as white powder.

LC-MS Method1: 347.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=6.48 (s, 1H), 4.31 (br d, J=11.0 Hz,1H), 4.22 (m, 1H), 4.03 (d, J=16.1 Hz, 1H), 3.93 (m, 1H), 3.66 (m, 1H),3.45 (s, 3H), 3.02 (m, 1H), 2.30-2.19 (m, 1H), 2.11 (m, 1H), 1.47-1.42(m, 1H), 1.35 (s, 3H), 1.30 (d, J=7.0 Hz, 9H)

Example 102(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[6a-methyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,2]oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanonetert-butyl(1R,5S,6r)-6-[6a-methyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,2]oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.3800 mmol) and 1-methylcyclopent-1-ene (0.61 mL, 5.75 mmol)in tert-Butyl methyl ether (4 mL) was added Et₃N (0.07 mL, 0.3800 mmol)in tert-Butyl methyl ether (1 mL) dropwise over 1 h. The mixture wasstirred at 20° C. for 5 hr. TLC (PE/EA=3/1) showed a major new spot(Rf=0.4) and the reaction was completed. The mixture was washed with H₂O(10 mL) and then extracted with EtOAc (10 mL×2). The combined organiclayer was dried over Na₂SO₄ and concentrated to give crude oil. Thecrude oil was purified by prep-TLC (PE/EA=3/1) to give the titlecompound (40 mg, 0.1305 mmol, 34.037% yield) as pale yellow solid.

LC-MS Method1 1.077 min, MS (m/z) 307.1 (M+H⁺).

3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-6a-methyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,2]oxazolehydrochloride A mixture of tert-butyl(1R,5S,6r)-6-[6a-methyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,2]oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(40 mg, 0.1300 mmol) in HCl/dioxane (5 mL, 4 M) was stirred at 20° C.for 2 hr. The mixture was concentrated to dryness with EA (15 mL)directly to give the title compound (26.9 mg, crude product) as paleyellow solid.

LC-MS Method1 0.535 min, MS (m/z) 207.0 (M+H⁺).

(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[6a-methyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,2]oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone

To a mixture of(3aR,6aR)-3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-6a-methyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,2]oxazolehydrochloride (26.9 mg, 0.1300 mmol) in DMF (1.5 mL) were added5-isopropyl-1H-pyrazole-3-carboxylic acid (20.1 mg, 0.1300 mmol), DIPEA(0.06 mL, 0.3900 mmol) and HATU (64.42 mg, 0.1700 mmol), and the mixturewas stirred at 20° C. for 16 hr. TLC (PE/EA=0/1) showed a major new spot(Rf=0.6) and the reaction was completed. The mixture was diluted withH₂O (10 mL) and EA (10 mL×2). The combined organic layer was separated,then dried over Na₂SO₄ and concentrated in vacuum to give crude oil. Thecrude oil was purified by prep-TLC (PE/EA=0/1) to give the titlecompound (28 mg, 0.0818 mmol, 62.702% yield) as pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ=13.05-12.79 (m, 1H), 6.37 (s, 1H), 4.35 (brdd, J=4.0, 12.0 Hz, 1H), 4.01-3.91 (m, 1H), 3.82 (br d, J=11.8 Hz, 1H),3.55-3.53 (m, 1H), 3.48 (br d, J=12.8 Hz, 1H), 3.12 (br d, J=3.3 Hz,1H), 2.97 (td, J=7.1, 13.7 Hz, 1H), 2.09-1.94 (m, 1H), 2.07-1.90 (m,1H), 1.90-1.73 (m, 4H), 1.68-1.49 (m, 3H), 1.42-1.30 (m, 4H), 1.22 (d,J=7.0 Hz, 8H).

Example 103(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

A 100 mL round-bottom flask was charged with5-isopropyl-1H-pyrazole-3-carboxylic acid (70 mg, 0.4500 mmol),N-ethyl-N-isopropylpropan-2-amine (0.24 mL, 1.41 mmol), HATU (190.94 mg,0.5000 mmol) and DMF (3 mL). After stirring for 30 min,(1R,5S,6r)-6-(5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane TFAsalt (126.33 mg, 0.4500 mmol) was added. The reaction mixture wasstirred at 20° C. for 16 hr to give a yellow solution. LCMS showed a newpeak gives the desired ms. H₂O (30 mL) was added and it was extractedwith EtOAc (30 mL×2). The combined organic layer was dried over Na₂SO₄and concentrated in vacuum to give a yellow oil. The crude was purifiedby Prep-HPLC (FA). The afforded flows were concentrated in vacuum toremove most of CH₃CN and lyophilized to give the title compound (13.52mg, 0.0448 mmol, 9.8741% yield) as white solid.

LC-MS Method1: 301.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ 6.48 (br s, 1H), 5.75 (s, 1H),4.21-4.33 (m, 2H), 3.96 (br dd, J=3.81, 10.94 Hz, 1H), 3.69 (br dd,J=3.69, 12.44 Hz, 1H), 3.04 (td, J=6.83, 13.73 Hz, 1H), 2.36 (s, 3H),2.15 (br d, J=3.38 Hz, 1H), 2.04-2.09 (m, 1H), 1.75 (t, J=3.06 Hz, 1H),1.30 (d, J=6.88 Hz, 6H)

Example 104{(1R,5S,6r)-6-[5-(difluoromethyl)-4-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanonetert-butyl(1R,5S,6r)-6-[1-hydroxypropyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg,2.37 mmol) in THF (10 mL) was added bromo(ethyl)magnesium (1.6 mL, 4.73mmol, 3M in Et₂O) drop-wise at −78° C. The reaction was allowed to warmto 0° C. and stirred for further 20 min to give pale yellow mixture. Thereaction was quenched with H₂O (15 mL), diluted with EA (30 mL) andacidified with 2N HCl to pH=5. The aqueous layer was extracted with EA(20 mL×2). The combined EA layer was dried over Na₂SO₄ and concentratedin vacuum to give the title compound (590 mg, 2.4448 mmol, crude) aspale yellow oil.

tert-butyl(1R,5S,6r)-6-propionyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of tert-butyl(1R,5S,6r)-6-[1-hydroxypropyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(590 mg, 2.44 mmol) and NaHCO₃ (410.77 mg, 4.89 mmol) in DCM (25 mL) wasadded Dess-Martin's reagent (1555.4 mg, 3.67 mmol) at 0° C. The mixturewas stirred at 20° C. for 12 h to give white mixture. The mixture wasdiluted with DCM (30 mL) and H₂O (20 mL) and basified with saturatedNaHCO₃ to pH=8. The aqueous layer was extracted with DCM (20 mL). Thecombined DCM layer was dried over Na₂SO₄ and concentrated in vacuum togive crude product which was purified by flash column (PE/EA=1/0 to 3/1)to give the title compound (500 mg, 2.0893 mmol, 85.461% yield) as paleyellow oil.

tert-butyl(1R,5S,6r)-6-(4-ethoxy-2-methyl-3,4-dioxobutanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-propionyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg,2.09 mmol) in THF (10 mL) was added LHMDS (2.5 mL, 2.51 mmol, 1 M inTHF) at −78° C. The reaction was stirred at −78° C. for 1 h. Then, asolution of diethyl oxalate (0.34 mL, 2.51 mmol) in THF (2 mL) was addedat −78° C. The reaction was allowed to warm to 20° C. and stirred forfurther 12 h to give pale yellow solution. The reaction was cooled to 0°C., diluted with EA (30 mL), quenched with H₂O (15 mL) and acidifiedwith 2M HCl to pH=6. The aqueous layer was extracted with EA (20 mL×2).The combined organic layer was dried over Na₂SO₄ and concentrated invacuum to give pale yellow oil. The crude oil was purified by flashcolumn (PE/EA=1/0 to 4/1) to give the title compound (300 mg, 0.8840mmol, 42.308% yield) as pale yellow oil. Meanwhile, about 160 mg ofB76-2a was recovered.

tert-butyl(1R,5S,6r)-6-[(1E)-4-ethoxy-N-hydroxy-2-methyl-3,4-dioxobutanimidoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of NaOH (42.43 mg, 1.06 mmol) in H₂O (2 mL) was addedhydroxylamine hydrochloride (0.04 mL, 1.06 mmol) at 0° C. After stirredfor 5 min, the reaction was added to a solution of tert-butyl(1R,5S,6r)-6-(4-ethoxy-2-methyl-3,4-dioxobutanoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(300 mg, 0.8800 mmol) in THF (2 mL) drop-wise at 0° C. The reaction wasstirred at 20° C. for 12 h to give pale yellow suspension. Thesuspension was diluted with EA (20 mL) and H₂O (10 mL) and adjusted with2M HCl to pH=7. The aqueous layer was extracted with EA (15 mL×2). Thecombined organic layer was dried over Na₂SO₄ and concentrated in vacuumto give the title compound (300 mg, 0.8465 mmol, 95.762% yield) as paleyellow oil.

tert-butyl(1R,5S,6r)-6-[5-(ethoxycarbonyl)-4-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(1E)-4-ethoxy-N-hydroxy-2-methyl-3,4-dioxobutanimidoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(300 mg, 0.8500 mmol) and Et₃N (0.15 mL, 1.1 mmol) in DCM (8 mL) wasadded methanesulfonyl chloride (126.06 mg, 1.1 mmol) at 0° C. Thereaction was stirred at 20° C. for 4 h to give pale yellow solution. Thereaction was cooled to 0° C. and treated with additional MsCl (60 uL)and Et₃N (0.8 mL). The reaction was stirred at 20° C. for further 1 h togive pale yellow solution. The reaction was concentrated in vacuum. Theresidue was purified by prep-TLC (PE/EA=3/1) to give the title compound(75 mg, 0.2230 mmol, 26.339% yield) as pale yellow gum.

¹H NMR (400 MHz, CHLOROFORM-d) δ=4.36 (q, J=6.8 Hz, 2H), 3.80-3.55 (m,2H), 3.50-3.40 (m, 2H), 2.23 (s, 3H), 2.15-2.10 (m, 1H), 2.10-2.00 (m,1H), 1.60-1.50 (m, 1H), 1.40 (s, 9H), 1.02 (t, J=6.8 Hz, 3H). tert-butyl(1R,5S,6r)-6-[5-(hydroxymethyl)-4-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[5-(ethoxycarbonyl)-4-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.3000 mmol) in THF (4 mL) was added LiALH₄ (20.33 mg, 0.5400mmol) at 0° C. The reaction was stirred at 0° C. for 20 min to givewhite mixture. The mixture was quenched with H₂O (3 drops), diluted withEA (20 mL) and stirred with Na₂SO₄ (10 g) for 10 min. The solid wasfiltered off. The filtrate was concentrated in vacuum to give the titlecompound (80 mg, 0.2718 mmol, 91.423% yield) as pale yellow oil.

tert-butyl(1R,5S,6r)-6-(5-formyl-4-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of tert-butyl(1R,5S,6r)-6-[5-(hydroxymethyl)-4-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(80 mg, 0.2700 mmol) and NaHCO₃ (57.08 mg, 0.6800 mmol) in DCM (4 mL)was added Dess-Martin reagent (172.91 mg, 0.4100 mmol) at 0° C. Themixture was stirred at 20° C. for 12 h to give white mixture. Themixture was diluted with DCM (15 mL) and H₂O (10 mL) and basified withsaturated NaHCO₃ to pH=8. The organic layer was collected, concentratedand purified by prep-TLC (PE/EA=3/1, rf-0.5) to give the title compound(45 mg, 0.1539 mmol, 56.639% yield) as colorless oil.

tert-butyl(1R,5S,6r)-6-[5-(difluoromethyl)-4-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-(5-formyl-4-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(45 mg, 0.1500 mmol) in DCM (3 mL) was added DAST (74.35 mg, 0.4600mmol) drop-wise at −78° C. The reaction was allowed to warm to 20° C.and stirred for further 12 h to give pale yellow solution. The reactionwas diluted with DCM (10 mL), cooled to 0° C., treated with H₂O (5 mL)and saturated NaHCO₃ (3 mL). The aqueous layer was extracted with EA (10mL×2). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuum to give the title compound (55 mg, 0.1750 mmol)as pale yellow oil.

(1R,5S,6r)-6-[5-(difluoromethyl)-4-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexaneTFA salt

A solution of tert-butyl(1R,5S,6r)-6-[5-(difluoromethyl)-4-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(55 mg, 0.1700 mmol) in DCM (2 mL) was treated with TFA (0.2 mL, 0.1700mmol) and stirred at 20° C. for 10 min to give pale brown solution. Thereaction was concentrated in vacuum to give the title compound (60 mg,0.2801 mmol, TFA salt) as pale brown oil.

{(1R,5S,6r)-6-[5-(difluoromethyl)-4-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of(1R,5S,6r)-6-[5-(difluoromethyl)-4-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexaneTFA salt (60 mg, 0.1800 mmol) and 5-isopropyl-1H-pyrazole-3-carboxylicacid (28.2 mg, 0.1800 mmol) in DMF (1 mL) were added HATU (69.93 mg,0.1800 mmol) and Et₃N (0.05 mL, 0.3700 mmol) at 0° C. The reaction wasstirred at 20° C. for 12 h to give pale yellow solution. The reactionwas concentrated in vacuum to give pale yellow oil, which was purifiedby prep-TLC (PE/EA=1/2) twice to give desired product. The product waslyophilized to give the title compound (21.2 mg, 0.0605 mmol, 33.078%yield) as a white solid.

LC-MS Method1: 350.9 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=10.05 (s, 1H), 6.78-6.48 (m, 1H), 6.45(s, 1H), 4.31 (br d, J=10.3 Hz, 1H), 4.21 (d, J=12.5 Hz, 1H), 3.92 (dd,J=4.4, 11.4 Hz, 1H), 3.64 (dd, J=4.3, 12.8 Hz, 1H), 2.96 (td, J=6.9,13.8 Hz, 1H), 2.29 (td, J=3.8, 7.4 Hz, 1H), 2.13 (td, J=3.7, 7.3 Hz,1H), 2.06 (t, J=2.0 Hz, 3H), 1.26-1.21 (m, 6H)

Example 105{(1R,5S,6r)-6-[4-(dimethylamino)-5-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanonetert-butyl(1R,5S,6r)-6-[4-(ethoxycarbonyl)-5-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

A round-bottom flask was charged with tert-butyl(1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(600 mg, 2.3 mmol), methyl 3-oxobutanoate (0.5 mL, 4.6 mmol) andtriethylamine (0.96 mL, 6.9 mmol) and DMF (12 mL). The reaction mixturewas stirred at 20° C. for 16 hr to give a yellow solution. LCMS showed amajor peak gives the desired ms. H₂O (30 mL) was added and it wasextracted with EtOAc (30 mL×2). The combined organic layer was driedover Na₂SO₄ and concentrated in vacuum to give the title compound (950mg, 2.947 mmol, 128.06% yield) as yellow oil. It was directly used inthe next step.

LC-MS Method1 0.925, MS (m/z) 308.0 (M−CH₂CH₃+H⁺).

5-methyl-3-[(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hex-6-yl]-1,2-oxazole-4-carboxylicacid

A 100 mL round-bottom flask was charged with tert-butyl(1R,5S,6r)-6-[4-(ethoxycarbonyl)-5-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(380 mg, 1.18 mmol), hydroxylithium hydrate (148.39 mg, 3.54 mmol) andTHF (6 mL). The reaction mixture was stirred at 20° C. for 16 hr to givea yellow solution. The reaction was diluted with H₂O (15 mL). pH wasadjusted to 3 with 1M HCl aq. and the reaction mixture was extractedwith EtOAc (30 mL×2). The combined organic layer was dried over Na₂SO₄and concentrated in vacuum to give the title compound (330 mg, 1.0703mmol, 90.794% yield) as yellow oil.

tert-butyl(1R,5S,6r)-6-(4-{[(benzyloxy)carbonyl]amino}-5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A round-bottom flask was charged with5-methyl-3-[(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hex-6-yl]-1,2-oxazole-4-carboxylicacid (300 mg, 0.9700 mmol), DPPA (401.65 mg, 1.46 mmol), Et₃N (0.41 mL,2.92 mmol) and Toluene (2.7273 mL). The reaction mixture was stirred at110° C. for 2 hr, and then phenylmethanol (0.4 mL, 3.89 mmol) was added.The reaction mixture was stirred at 110° C. for 10 min to give a yellowsolution. H₂O (30 mL) was added and it was extracted with EtOAc (30mL×2). The combined organic layer was dried over Na₂SO₄ and concentratedin vacuum to give a yellow oil. The crude was purified by silica gelchromatography (PE/EA=10/1 to 3/1) to give the title compound (160 mg,0.3870 mmol, 39.771% yield) as yellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.45-7.20 (m, 5H), 5.12 (brs, 2H),3.80-3.25 (m, 4H), 2.25 (brs, 3H), 2.00-1.90 (m, 1H), 1.50-1.40 (m, 1H),1.39 (s, 9H).

tert-butyl(1R,5S,6r)-6-(4-amino-5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A round-bottom flask was charged with tert-butyl(1R,5S,6r)-6-(4-{[(benzyloxy)carbonyl]amino}-5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(1200 mg, 2.9 mmol), Pd/C (120 mg, 2.9 mmol) and MeOH (10 mL). Thereaction mixture was stirred under molecular hydrogen (15 psi)atmosphere to give a black suspension. The suspension was filtratedthrough a pad of celite and the filtrate was concentrated in vacuum togive the title compound as yellow solid.

LC-MS Method1 0.765 min, MS (m/z) 280.1 (M+H⁺).

tert-butyl(1R,5S,6r)-6-[4-(dimethylamino)-5-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-(4-amino-5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.3600 mmol) in MeOH (2.8571 mL) was added formaldehyde (1 mL,2.15 mmol). After stirring for 15 min, sodium NaBH₃CN (134.98 mg, 2.15mmol) was added to give a yellow solution. H₂O (30 mL) was added and itwas extracted with EtOAc (30 mL×2). The combined organic layer driedover Na₂SO₄ and concentrated in vacuum to give the title compound (150mg, crude) as yellow oil. It was directly used in the next step.

3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-N,N,5-trimethyl-1,2-oxazol-4-amineTFA salt

A round-bottom flask was charged with tert-butyl(1R,5S,6r)-6-[4-(dimethylamino)-5-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(150 mg, 0.4900 mmol), 2,2,2-trifluoroacetic acid (0.04 mL, 0.4900mmol), DCM (6 mL) and 2,2,2-trifluoroacetic acid (0.04 mL, 0.4900 mmol).The reaction mixture was stirred at 30° C. under N₂ protection to give ayellow solution. The reaction mixture was evaporated in vacuum to givethe title compound (220 mg, 0.5054 mmol, 103.56% yield) as yellow oil.It was directly used in the next step.

LC-MS Method1 0.443 min, MS (m/z) 207.9 (M+H⁺).

{(1R,5S,6r)-6-[4-(dimethylamino)-5-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (80 mg,0.5200 mmol) and HATU (238.05 mg, 0.6200 mmol) in DMF (2 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.36 mL, 2.08 mmol). After stirringfor 15 min,3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-N,N,5-trimethyl-1,2-oxazol-4-amineTFA salt (225.89 mg, 0.5200 mmol) was added and the reaction mixture wasstirred for 16 hr to give a yellow solution. H₂O (30 mL) was added andit was extracted with EtOAc (30 mL×2). The combined organic layer wasdried over Na₂SO₄ and concentrated in vacuum to give a yellow oil. Thecrude was purified by Prep-HPLC (NH₃). The afforded flows wereconcentrated in vacuum to remove most of CH₃CN and lyophilized to givethe title compound (38.86 mg, 0.1132 mmol, 21.807% yield) as whitesolid.

LC-MS Method1: 344.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ 6.49 (s, 1H), 4.19-4.37 (m, 2H), 3.99(dd, J=4.39, 11.17 Hz, 1H), 3.71 (dd, J=4.52, 12.55 Hz, 1H), 3.03 (td,J=7.00, 13.87 Hz, 1H), 2.71 (s, 6H), 2.32-2.40 (m, 4H), 2.14 (td,J=3.83, 7.40 Hz, 1H), 1.68 (t, J=3.51 Hz, 1H), 1.30 (d, J=7.03 Hz, 6H)

Example 106(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[5-methyl-4-(2-pyridinyl)-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanonetert-butyl(1R,5S,6r)-6-[5-methyl-4-(2-pyridinyl)-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-(4-bromo-5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.29 mmol) in 1,4-Dioxane (2 mL) were addedtributyl(2-pyridyl)stannane (214.52 mg, 0.58 mmol), X-Phos (27.78 mg,0.0600 mmol) and X-Phos-Pd-G2 (22.92 mg, 0.0300 mmol) under N₂. Theresulting mixture was stirred at 110° C. for 16 hours to give a blackbrown solution. LCMS showed the reaction was completed. The reaction wasdiluted with EA (15 mL) and filtered through a pad of Celite. Thefiltrate was concentrated and the residue was purified by prep-TLC(EA/PE=1/1, Rf=0.5) to afford the title compound (71 mg, 71.379% yield)as a light yellow solid.

(1R,5S,6r)-6-[5-methyl-4-(2-pyridinyl)-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexanehydrochloride

A solution of tert-butyl(1R,5S,6r)-6-[5-methyl-4-(2-pyridinyl)-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(71 mg, 0.2100 mmol) in 4M HCl in MeOH (1 mL, 0.2100 mmol) was stirredat 15° C. for 10 min to give a light yellow solution. TLC showed thestarting material was consumed up and a new spot was detected. Thereaction was concentrated to afford the title compound (62 mg, 123.55%yield) as a light yellow gum.

(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[5-methyl-4-(2-pyridinyl)-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone

To a solution of(1R,5S,6r)-6-[5-methyl-4-(2-pyridinyl)-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexanehydrochloride (62 mg, 0.26 mmol) in DMF (1 mL) were added5-isopropyl-1H-pyrazole-3-carboxylic acid (39.61 mg, 0.26 mmol), DIPEA(0.13 mL, 0.77 mmol) and HATU (146.46 mg, 0.39 mmol) at 0 to 5° C. Theresulting mixture was stirred at 15° C. for 16 hours to give a lightbrown solution. The reaction was diluted with H₂O (15 mL) and extractedwith EA (5 mL×3). The combined organic layers were washed with NH₄Cl aq.(5 mL×2) and brine (5 mL), dried over Na₂SO₄, filtered and concentratedto dryness. The residue was purified by prep-TLC (EA/MeOH=12/1, Rf=0.6)and lyophilized to afford the title compound (34 mg, 35.057% yield) as awhite solid.

LC-MS Method1: 378.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.88 Hz, 6H) 1.92 (t,J=3.44 Hz, 1H) 2.18 (dt, J=7.41, 3.86 Hz, 1H) 2.46 (dt, J=7.44, 3.91 Hz,1H) 2.55 (s, 3H) 2.97-3.08 (m, 1H) 3.73 (dd, J=12.69, 4.44 Hz, 1H) 3.99(dd, J=11.13, 4.38 Hz, 1H) 4.20 (d, J=12.76 Hz, 1H) 4.28 (br d, J=11.13Hz, 1H) 6.44 (s, 1H) 7.23 (dd, J=7.32, 5.19 Hz, 1H) 7.38 (d, J=7.88 Hz,1H) 7.75 (td, J=7.75, 1.75 Hz, 1H) 8.66 (d, J=4.63 Hz, 1H)

Example 107[(1R,5S,6r)-6-{4-[1-(cyclopropylmethyl)-1H-pyrazol-3-yl]-5-methyl-1,2-oxazol-3-yl}-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone3-bromo-1-(cyclopropylmethyl)-1H-pyrazole

To a solution of 3-bromopyrazole (1.g, 6.8 mmol) in DMF (10 mL) wereadded K₂CO₃ (1.88 g, 13.61 mmol) and (bromomethyl)cyclopropane (0.66 mL,6.8 mmol). The reaction was stirred at 15° C. for 3 hours to give awhite suspension. LCMS showed about half of the starting material wasremained and the reaction was stirred for 16 hours to give a whitesuspension. TLC (PE/EA=5/1, Rf=0.7, I₂) showed most of the startingmaterial was consumed and a new spot was detected. The reaction wasdiluted with H₂O (90 mL) and extracted with EA (10 mL×3). The combinedorganic layers were washed with NH₄Cl aq. (10 mL) and brine (10 mL),dried over Na₂SO₄, filtered and concentrated to afford a mixture of thetitle compounds and its isomer as colorless oil (1.36 g, 99.413% yield).

Isomer a: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49 (d, J=1.2 Hz, 1H),6.28 (d, J=1.2 Hz, 1H), 4.03 (d, J=6.8 Hz, 2H), 1.40-1.20 (m, 2H),0.60-0.50 (m, 1H), 0.45-0.40 (m, 1H). Isomer b; ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.39 (d, J=1.2 Hz, 1H), 6.26 (d, J=1.2 Hz, 1H), 3.92(d, J=6.8 Hz, 2H), 1.40-1.20 (m, 2H), 0.70-0.60 (m, 1H), 0.40-0.35 (m,1H). 1-(cyclopropylmethyl)-3-(tributylstannyl)-1H-pyrazole

To a solution of the mixture of3-bromo-1-(cyclopropylmethyl)-1H-pyrazole and its isomer (1.39 g, 6.91mmol) in THF (15 mL) was added n-BuLi (3.04 mL, 7.6 mmol) dropwise at−75 to −70° C. After stirring for 1 hour at −75 to −70° C.,tributyl(chloro)stannane (2.48 g, 7.6 mmol) in THF (5 mL) was added tothe reaction at −75 to −70° C. The resulting mixture was stirred at 15°C. for 16 hours to give a light yellow solution. The reaction wasquenched with NH₄C1 aq (5 mL). The mixture was diluted with H₂O (50 mL)and extracted with EA (15 mL×3). The combined organic layers were washedwith brine (15 mL), dried over Na₂SO₄, filtered and concentrated todryness. The residue was purified by flash column (eluted with 5% EA inPE, EA/PE=1/9) to afford the title compound (525 mg, Rf=0.45) ascolorless oil.

LC-MS Method1 1.060 min, MS (m/z) 413.0 (M+H⁺).

tert-butyl(1R,5S,6r)-6-{4-[1-(cyclopropylmethyl)-1H-pyrazol-3-yl]-5-methyl-1,2-oxazol-3-yl}-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-(4-bromo-5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(300 mg, 0.87 mmol) in 1,4-Dioxane (3 mL) were added1-(cyclopropylmethyl)-3-(tributylstannyl)-1H-pyrazole (431.31 mg, 1.05mmol), X-Phos (83.34 mg, 0.17 mmol) and X-Phos-Pd-G2 (68.77 mg, 0.09mmol) under N₂. The resulting mixture was stirred at 100° C. for 16hours to give a black brown solution. The reaction was diluted with EA(30 mL) and filtered through a pad of celite. The filtrate wasconcentrated and purified by flash column (8% EA in PE, PE/EA=3/1,Rf=0.5) to afford the title compound (205 mg, 16.47% yield) as a lightyellow solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50 (d, J=2.0 Hz, 1H), 6.40 (d,J=2.0 Hz, 1H), 4.00 (d, J=3.2 Hz, 2H), 3.79 (d, J=11.2 Hz, 1H), 3.70 (d,J=11.2 Hz, 1H), 3.50-3.40 (m, 2H), 2.38 (s, 3H), 2.11 (m, 2H), 1.70-1.65(m, 1H), 1.47 (s, 9H), 0.70-0.60 (m, 1H), 0.55-0.50 (m, 2H), 0.45-0.35(m, 2H).

(1R,5S,6r)-6-{4-[1-(cyclopropylmethyl)-1H-pyrazol-3-yl]-5-methyl-1,2-oxazol-3-yl}-3-azabicyclo[3.1.0]hexanehydrochloride

A solution of tert-butyl(1R,5S,6r)-6-{4-[1-(cyclopropylmethyl)-1H-pyrazol-3-yl]-5-methyl-1,2-oxazol-3-yl}-3-azabicyclo[3.1.0]hexane-3-carboxylate(205 mg, 0.5300 mmol) in 4M HCl in MeOH (3 mL, 0.5300 mmol) was stirredat 15° C. for 15 min to give a colorless solution. LCMS showed thestarting material was consumed up and one new peak with desired mass wasdetected. The reaction was concentrated to afford the title compound(77.8 mg, 51.312% yield) as an off-white solid.

LC-MS Method1 0.652 min, MS (m/z) 284.9 (M+H⁺).

[(1R,5S,6r)-6-{4-[1-(cyclopropylmethyl)-1H-pyrazol-3-yl]-5-methyl-1,2-oxazol-3-yl}-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of(1R,5S,6r)-6-{4-[1-(cyclopropylmethyl)-1H-pyrazol-3-yl]-5-methyl-1,2-oxazol-3-yl}-3-azabicyclo[3.1.0]hexanehydrochloride (77.8 mg, 0.27 mmol) in DMF (1 mL) were added5-isopropyl-1H-pyrazole-3-carboxylic acid (42.18 mg, 0.27 mmol), DIPEA(0.23 mL, 1.37 mmol) and HATU (155.95 mg, 0.41 mmol). The resultingmixture was stirred at 15° C. for 16 hours to give a brown solution. Thereaction was diluted with H₂O (20 mL) and extracted with EA (5 mL×3).The combined organic layers were washed with NH₄Cl aq. (8 mL) and brine(8 mL), dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by prep-TLC (EA/MeOH=10/1) and lyophilized toafford the title compound (21.33 mg, 18.54% yield) as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.35 (q, J=5.02 Hz, 2H) 0.57-0.66(m, 2H) 1.21-1.27 (m, 1H) 1.30 (d, J=7.03 Hz, 7H) 2.00 (t, J=3.51 Hz,1H) 2.18 (dt, J=7.40, 3.83 Hz, 1H) 2.41 (dt, J=7.40, 3.83 Hz, 1H) 2.52(s, 3H) 3.02 (dt, J=13.74, 6.81 Hz, 1H) 3.71 (dd, J=12.67, 4.39 Hz, 1H)3.97 (d, J=7.03 Hz, 2H) 4.21-4.34 (m, 2H) 6.31 (d, J=2.26 Hz, 1H) 6.46(s, 1H) 7.53 (d, J=2.26 Hz, 1H)

Example 108[(1R,5S,6r)-6-(1,2-benzoxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone[(1R,5S,6r)-6-(1,2-benzoxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (10.75 mg,0.0700 mmol) in DMF (1 mL) were added HATU (33.71 mg, 0.0900 mmol),DIPEA (0.03 mL, 0.1900 mmol) and3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-1,2-benzoxazole (15 mg,0.0600 mmol). The mixture was stirred at 20° C. for 12 h to give yellowsolution. LCMS showed the desired MS. The reaction mixture was pouredinto H₂O (15 mL) and extracted with EtOAc (20 mL×4). The combinedorganic layers were washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-TLC (PE:EtOAc=1:1) and lyophilized to give the titlecompound (5.1 mg, 0.0152 mmol, 23.924% yield) as white solid.

¹H NMR (400 MHz, DMSO-d6) δ ppm 12.96 (br s, 1H), 7.99 (br d, J=7.78 Hz,1H), 7.56-7.75 (m, 2H), 7.36 (br t, J=7.78 Hz, 1H), 6.42 (s, 1H), 4.50(br d, J=12.05 Hz, 1H), 4.10 (br d, J=12.30 Hz, 1H), 3.96 (br d, J=11.80Hz, 1H), 3.61 (br d, J=8.03 Hz, 1H), 2.93-3.04 (m, 1H), 2.42 (br s, 1H),2.22 (br s, 1H), 1.23 (br d, J=6.53 Hz, 6H)

Example 109(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (72.64 mg,0.4700 mmol) in DMF (3.5385 mL) was added HATU (135.48 mg, 0.7100 mmol).The reaction mixture was stirred at 15° C. for 30 min. Then(1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane(92 mg, 0.4700 mmol) was added. The reaction mixture was stirred at 15°C. for 0.5 hr to give a yellow mixture. LCMS showed the desired MS. Thereaction mixture was purified by prep-HPLC (NH₃) to give the titlecompound (14.45 mg, 0.0436 mmol, 9.254% yield) as white powder.

LC-MS Method1: 332.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=10.62 (br s, 1H), 6.49 (s, 1H), 4.35(br d, J=10.4 Hz, 1H), 4.22 (d, J=12.8 Hz, 1H), 3.99-3.89 (m, 1H), 3.65(dd, J=4.0, 12.8 Hz, 1H), 3.02 (m, 1H), 2.78 (s, 3H), 2.33 (m, 1H), 2.04(m, 1H), 1.41 (d, J=7.3 Hz, 6H), 1.30 (d, J=7.0 Hz, 6H), 1.14 (t, J=3.5Hz, 1H)

Example 110[(1R,5S,6r)-6-(4-ethyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone[(1R,5S,6r)-6-(4-ethyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (69.24 mg,0.4500 mmol) in DMF (3.373 mL) were added HATU (129.15 mg, 0.6700 mmol)and DIPEA (171.4 mg, 1.35 mmol). The reaction mixture was stirred at 15°C. for 30 min. Then(1R,5S,6r)-6-(4-ethyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (94 mg, 0.4500 mmol) was added. The reaction mixture wasstirred at 15° C. for 0.5 hr to give a yellow mixture. LCMS showed thedesired MS. The reaction mixture was purified by prep-HPLC (NH₃) to givethe title compound (41.23 mg, 0.1194 mmol, 26.574% yield) as whitepowder.

LC-MS Method1: 346.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=10.80 (br s, 1H), 6.50 (s, 1H), 4.35(br s, 1H), 4.21 (d, J=12.8 Hz, 1H), 3.97 (dd, J=4.3, 11.6 Hz, 1H), 3.67(dd, J=4.4, 12.8 Hz, 1H), 3.18 (q, J=7.3 Hz, 2H), 3.02 (td, J=6.9, 13.8Hz, 1H), 2.41 (td, J=3.9, 7.4 Hz, 1H), 2.05 (td, J=3.6, 7.2 Hz, 1H),1.43 (d, J=12.8 Hz, 6H), 1.30 (d, J=6.8 Hz, 6H), 1.20 (t, J=7.2 Hz, 3H),1.14 (t, J=3.4 Hz, 1H)

Example 111[(1R,5S,6r)-6-(4-cyclopropyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone[(1R,5S,6r)-6-(4-cyclopropyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of(1R,5S,6r)-6-(4-cyclopropyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (90 mg, 0.41 mmol), 5-isopropyl-1H-pyrazole-3-carboxylic acid(68.9 mg, 0.45 mmol) and DIPEA (0.34 mL, 2.03 mmol) in DMF (4 mL) wasadded HATU (171 mg, 0.45 mmol). The mixture was stirred at 20° C. for 16h. The reaction mixture was diluted with H₂O (50 mL) and extracted by EA(25 mL×3). The organic phase was washed with brine (50 mL×3), dried overanhydrous Na₂SO₄ and concentrated to give a residue. The residue waspurified by Prep-HPLC (NH₃) to afford the title compound (20 mg, 0.056mmol, 13.7% yield) as a white solid.

LC-MS Method1: 358.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.39 (br s, 1H) 6.51 (s, 1H)4.14-4.39 (m, 2H) 3.96 (dd, J=11.4, 4.4 Hz, 1H) 3.69 (dd, J=12.6, 4.4Hz, 1H) 3.03 (spt, J=6.9 Hz, 1H) 2.28-2.37 (m, 2H) 2.06 (dt, J=7.2, 3.8Hz, 1H) 1.48 (d, J=8.9 Hz, 6H) 1.43 (t, J=3.5 Hz, 1H) 1.31 (d, J=6.9 Hz,6H) 0.67-0.77 (m, 4H) 25 [0614]

Example 112[(1R,5S,6r)-6-(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanoneN-phenyl-2-propanimine

To a solution of aniline (0.2 mL, 2.15 mmol) in Toluene (4.6 mL) wasadded acetone (374.19 mg, 6.44 mmol), followed by 4A MS (200 mg). Thenthe mixture was stirred at 110° C. for 3 h. The mixture was filtered andthe filtrate was concentrated to dryness to give the title compound (300mg, crude) as yellow oil, which was used to next step withoutpurification.

tert-butyl(1R,5S,6r)-6-(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(115.23 mg, crude) in DMF (3 mL) was added Et₃N (0.3 mL, 2.34 mmol),followed by N-phenyl-2-propanimine (186.64 mg, crude) at 20° C. and thenthe mixture was stirred at 25° C. for 1 h. The mixture was poured intoH₂O (5 mL) and extracted with EtOAc (5 mL×5). The combined organic layerwas washed with brine (5 mL), dried over Na₂SO₄ and concentrated todryness. The residue was purified by silica gel column (EA in PE from 0%to 50%) to give the title compound (140 mg, 0.3917 mmol, 83.849% yield)as white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.40-7.20 (m, 3H), 7.20-7.10 (m,2H), 3.50-3.25 (m, 4H), 2.25-2.00 (m, 2H), 1.40 (brs, 3H), 1.37 (brs,3H), 1.30 (s, 9H), 0.89 (s, 1H).

(1R,5S,6r)-6-(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt

A solution of tert-butyl(1R,5S,6r)-6-(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(70 mg, 0.20 mmol) in TFA (0.5 mL)/DCM (2.5 mL) was stirred at 20° C.for 0.5 h. The mixture was concentrated to give the title compound (73mg, crude as TFA salt) which was used to next step without purification.

[(1R,5S,6r)-6-(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of 3-isopropyl-1H-pyrazole-5-carboxylic acid (39.4 mg,0.26 mmol) and Et₃N (0.17 mL, 0.98 mmol) in DMF (2 mL) was added HATU(89.64 mg, 0.24 mmol) at 15° C. and then the mixture was stirred at 15°C. for 20 min. To the mixture was added(1R,5S,6r)-6-(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (73 mg, crude as TFA salt) at 15° C. and then the resultingmixture was stirred at 15° C. for 16 h. The mixture was concentrated toremove Et₃N and the residue was purified by prep-HPLC (NH₃) and thenlyophilized for 16 h to give the title compound (40.08 mg, 0.1019 mmol,51.816% yield) as white solid.

LC-MS Method1: 394.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=10.32 (brs, 1H), 7.44-7.32 (m, 3H),7.19 (d, J=7.6 Hz, 2H), 6.43 (s, 1H1), 4.30-4.00 (m, 1H), 3.97-3.90 (m,2H), 3.65 (dd, J=4.4, 12.8 Hz, 1H), 3.05-2.96 (m, 1H), 2.48-2.40 (m,1H), 2.22-2.15 (m, 1H), 1.51 (s, 3H), 1.45 (s, 3H), 1.29 (d, J=6.8 Hz,6H), 0.99 (t, J=3.2 Hz, 1H).

Example 113{(1R,5S,6r)-6-[5,5-dimethyl-4-(3-methylphenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanone{(1R,5S,6r)-6-[5,5-dimethyl-4-(3-methylphenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (57.61 mg,0.3700 mmol) in DMF (2 mL) were added HATU (166.66 mg, 0.4400 mmol),DIPEA (0.18 mL, 1.09 mmol) and(1R,5S,6r)-6-[5,5-dimethyl-4-(3-methylphenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexaneTFA salt (120 mg, 0.3100 mmol, TFA salt). The mixture was stirred at 20°C. for 12 h to give yellow solution. The mixture was poured into H₂O (15mL) and extracted with EtOAc (15 mL×5). The combined organic layer waswashed with brine (50 mL), dried over Na₂SO₄ and concentrated todryness. The residue was purified by prep-TLC (EtOAc) and lyophilized togive the title compound (65.74 mg, 0.1613 mmol, 51.808% yield) as whitesolid.

LC-MS Method1: 408.1 [M+H⁺]

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.97-10.66 (1H, m), 7.24-7.27 (1H,m), 7.13 (1H, d, J=7.75 Hz), 6.92-7.00 (2H, m), 6.40 (1H, s), 4.11 (1H,br d, J=10.88 Hz), 3.87-3.97 (2H, m), 3.64 (1H, dd, J=12.69, 4.44 Hz),2.94-3.06 (1H, m), 2.38-2.47 (1H, m), 2.37 (3H, s), 2.18 (1H, dt,J=7.35, 3.77 Hz), 1.49 (3H, s), 1.43 (3H, s), 1.28 (6H, d, J=6.88 Hz),0.97 (1H, t, J=3.50 Hz)

Example 114{(1R,5S,6r)-6-[5,5-dimethyl-4-(4-methylphenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanoneN-(4-methylphenyl)-2-propanimine

To a solution of 4-amino toluene (0.18 mL, 1.87 mmol) in Toluene (4 mL)was added acetone (325.23 mg, 5.6 mmol), followed by 4A MS (200 mg).Then the mixture was stirred at 110° C. for 5 h. Without monitoring. Themixture was filtered and the filtrate was concentrated to dryness togive the title compound (300 mg, crude) as yellow oil, which was used tonext step without purification.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (d, J=8.0 Hz, 2H), 7.09 (d,J=8.0 Hz, 2H), 3.53 (brs, 6H), 2.35 (s, 3H).

tert-butyl(1R,5S,6r)-6-[5,5-dimethyl-4-(4-methylphenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(115.23 mg, crude reaction from above) in DMF (3 mL) was added Et₃N (0.3mL, 2.34 mmol), followed by N-(4-methylphenyl)-2-propanimine (206.3 mg,crude) at 20° C. and then the mixture was stirred at 25° C. for 1 h. Themixture was poured into H₂O (5 mL) and extracted with EtOAc (5 mL×5).The combined organic layer was washed with brine (5 mL), dried overNa₂SO₄ and concentrated to dryness. The residue was purified by silicagel column (EA in PE from 0% to 50%) to give the title compound (150 mg,0.4038 mmol, 86.448% yield) as white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21 (d, J=8.0 Hz, 2H), 7.06 (d,J=8.0 Hz, 2H), 3.50-3.30 (m, 4H), 2.39 (s, 3H), 2.20-2.10 (m, 1H),2.10-2.00 (m, 1H), 1.47 (s, 6H), 1.38 (s, 9H), 0.95-0.90 (m, 1H).(1R,5S,6r)-6-[5,5-dimethyl-4-(4-methylphenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexaneTFA salt

A solution of tert-butyl(1R,5S,6r)-6-[5,5-dimethyl-4-(4-methylphenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(120 mg, 0.3200 mmol) in TFA (1 mL)/DCM (5 mL) was stirred at 20° C. for0.5 h. The mixture was concentrated to give the title compound (124.49mg, crude), it was used to next step without purification.

{(1R,5S,6r)-6-[5,5-dimethyl-4-(4-methylphenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of 3-isopropyl-1H-pyrazole-5-carboxylic acid (64.49 mg,0.420 mmol) and Et₃N (0.28 mL, 1.61 mmol) in DMF (2 mL) was added HATU(158.95 mg, 0.420 mmol) at 15° C. and then the mixture was stirred at15° C. for 20 min. To the mixture was added(1R,5S,6r)-6-[5,5-dimethyl-4-(4-methylphenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexaneTFA salt (124 mg, 0.320 mmol, TFA salt) at 15° C. and then the resultingmixture was stirred at 15° C. for 2 h. The mixture was concentrated toremove Et₃N (about 3 mL of DMF remained). Precipitate solids werecollected by filtration and the cake was washed with MeCN (0.5 mL×2) togive the title compound (18.1 mg, 0.0444 mmol, 13.804% yield) as whitesolid. The filtrate was purified by prep-HPLC (NH₃) and then lyophilizedto give the title compound (34.44 mg, 0.0845 mmol, 26.266% yield) aswhite solid.

LC-MS Method1: 408.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=10.75-9.95 (m, 1H), 7.20 (br d, J=8.0Hz, 1H), 7.07 (d, J=8.0 Hz, 2H), 6.62-6.17 (m, 1H), 4.40-3.55 (m, 4H),3.11-2.93 (m, 1H), 2.49-2.05 (m, 5H), 1.45 (d, J=27.6 Hz, 6H), 1.29 (d,J=7.2 Hz, 6H), 0.96 (t, J=3.2 Hz, 1H).

Example 115(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[4-(4-methoxyphenyl)-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanoneN-(4-methoxyphenyl)propan-2-imine

To a solution of 4-methoxyaniline (0.83 mL, 8.12 mmol) in toluene (10mL) was added acetone (1.41 g, 24.36 mmol), followed by 4A MS (1.g, 8.12mmol). Then the mixture was stirred at 110° C. for 5 h to give brownsuspension. The mixture was filtered and the filtrate was concentratedto dryness to give the title compound (1.5 g, 9.1901 mmol, 113.18%yield) as brown oil, which was used to next step without purification.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.75 (d, J=8.0 Hz, 2H), 6.65 (d,J=8.0 Hz, 2H), 3.77 (s, 3H), 2.15 (s, 6H). tert-butyl(1R,5S,6r)-6-[4-(4-methoxyphenyl)-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylatein DMF (2 mL) was added Et₃N (0.48 mL, 2.88 mmol), followed byN-(4-methoxyphenyl)propan-2-imine (375.62 mg, 2.3 mmol) at 20° C. andthen the mixture was stirred at 25° C. for 1 h to give brown solution.The mixture was poured into H₂O (15 mL) and extracted with EtOAc (15mL×5). The combined organic layer was washed with brine (50 mL), driedover Na₂SO₄ and concentrated to dryness. The residue was purified bysilica gel column (EA in PE from 0% to 50%) to give the title compound(140 mg, 0.3613 mmol, 62.802% yield) as brown oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.11 (d, J=8.0 Hz, 2H), 6.93 (d,J=8.0 Hz, 2H), 3.83 (s, 3H), 3.50-3.30 (m, 4H), 2.20-2.10 (m, 1H),2.10-2.00 (m, 1H), 1.45 (s, 3H), 1.42 (s, 3H), 1.40 (s, 9H), 0.95-0.90(m, 1H).(1R,5S,6r)-6-[4-(4-methoxyphenyl)-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexaneTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-[4-(4-methoxyphenyl)-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(140 mg, 0.3600 mmol) in DCM (5 mL) was added TFA (1 mL, 13.46 mmol).The mixture was stirred at 20° C. for 0.5 h to give black solution. TLC(PE:EtOAc=1:1) showed the reaction was completed. The reaction mixturewas concentrated directly to give the title compound (140 mg, 0.3488mmol, 96.534% yield, TFA, salt) as brown gum.

(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[4-(4-methoxyphenyl)-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (64.53 mg,0.4200 mmol) in DMF (2 mL) were added HATU (186.68 mg, 0.4900 mmol),DIPEA (0.2 mL, 1.22 mmol) and(1R,5S,6r)-6-[4-(4-methoxyphenyl)-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexaneTFA salt (140 mg, TFA, salt 0.3500 mmol). The mixture was stirred at 20°C. for 12 h to give brown solution. The mixture was poured into H₂O (15mL) and extracted with EtOAc (15 mL×5). The combined organic layer waswashed with brine (50 mL), dried over Na₂SO₄ and concentrated todryness. The residue was purified by prep-HPLC (FA). The afforded flowswere combined, concentrated to remove most of CH₃CN and lyophilized togive the title compound (59.06 mg, 0.1395 mmol, 39.981% yield) as brownsolid.

LC-MS Method1: 404.3 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.11 (2H, d, J=8.76 Hz), 6.91 (2H,d, J=8.75 Hz), 6.39 (1H, s), 4.92 (2H, br s), 3.96-4.06 (1H, m),3.84-3.95 (2H, m), 3.83 (3H, s), 3.62 (1H, br dd, J=12.63, 4.25 Hz),3.06 (1H, dt, J=13.88, 6.94 Hz), 2.35-2.45 (1H, m), 2.12-2.23 (1H, m),1.44 (6H, d, J=15.01 Hz), 1.30 (6H, d, J=6.88 Hz), 0.97 (1H, t, J=3.13Hz)

Example 116(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[4-(3-methoxyphenyl)-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[4-(3-methoxyphenyl)-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (64.53 mg,0.4200 mmol) in DMF (2 mL) were added HATU (186.68 mg, 0.4900 mmol),DIPEA (0.2 mL, 1.22 mmol) and(1R,5S,6r)-6-[4-(3-methoxyphenyl)-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexaneTFA salt (140 mg, 0.3500 mmol, TFA salt). The mixture was stirred at 20°C. for 12 h to give brown solution. The mixture was poured into H₂O (15mL) and extracted with EtOAc (15 mL×5). The combined organic layer waswashed with brine (50 mL), dried over Na₂SO₄ and concentrated todryness. The residue was purified by prep-HPLC (NH₃). The afforded flowswere combined, concentrated to remove most of CH₃CN and lyophilized togive the title compound (62.38 mg, 0.1473 mmol, 42.229% yield) to givewhite solid.

LC-MS Method1: 424.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.34 (1H, br s), 7.28-7.33 (1H,m), 6.86 (1H, dd, J=8.41, 1.88 Hz), 6.75 (1H, dd, J=7.91, 1.13 Hz), 6.70(1H, t, J=2.13 Hz), 6.45-6.45 (1H, m), 6.42 (1H, br s), 4.14 (1H, br s),3.88-3.99 (2H, m), 3.82 (3H, s), 3.65 (1H, dd, J=12.80, 4.27 Hz), 3.00(1H, dt, J=13.80, 6.90 Hz), 2.42 (1H, dt, J=7.47, 3.92 Hz), 2.14-2.21(1H, m), 1.42-1.53 (6H, m), 1.28 (6H, d, J=6.78 Hz), 1.02 (1H, t, J=3.39Hz)

Example 117[(1R,5S,6r)-6-(4-benzyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanoneN-benzyl-2-propanimine

To a solution of benzylamine (0.5 mL, 4.67 mmol) and acetone (1 mL, 14mmol) in Toluene (5 mL) was added 4AMS (3 g), and the mixture wasstirred at 110° C. for 4 h without monitor. The mixture was filtered andthe filtrate was concentrated to give the title compound (330 mg, 2.24mmol) as a colorless oil. The product was used directly for next step.

tert-butyl(1R,5S,6r)-6-(4-benzyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(150 mg, 0.58 mmol) and Et₃N (0.29 mL, 1.73 mmol) in DMF (2 mL) wasadded N-benzyl-2-propanimine (330 mg, 2.24 mmol). The mixture wasstirred at 20° C. for 2 h. The reaction was diluted with H₂O (50 mL) andextracted by EtOAc (20 mL×3). The organic phase was washed three timeswith brine, dried over anhydrous Na₂SO₄ and concentrated to give aresidue. The residue was purified by flash column (PE:EA=1:0-1:1) togive the title compound (50 mg, 0.1346 mmol, 23.3% yield) (PE:EA=3:1,Rf=0.5) as a pale yellow solid.

(1R,5S,6r)-6-(4-benzyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-(4-benzyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(50 mg, 0.13 mmol) in DCM (3 mL) was added TFA (0.3 mL, 4.04 mmol), andthe mixture was stirred at 20° C. for 1 h. The reaction mixture wasconcentrated to give the title compound (50 mg, 0.18 mmol) as a yellowoil.

[(1R,5S,6r)-6-(4-benzyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of(1R,5S,6r)-6-(4-benzyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexaneTFA salt (50 mg, 0.1800 mmol), HATU (84.5 mg, 0.22 mmol) and DIPEA (0.15mL, 0.92 mmol) in DMF (3 mL) was added5-isopropyl-1H-pyrazole-3-carboxylic acid (34.0 mg, 0.22 mmol), and themixture was stirred at 20° C. for 16 hr. The mixture was diluted withH₂O (30 mL) and extracted by EA (20 mL×2), and the organic phase waswashed by brine (30 mL×3), dried over anhydrous Na₂SO₄ and concentratedto give a residue. The residue was purified by Prep-HPLC (FA) to affordthe title compound (2.5 mg) as a white solid.

LC-MS Method1: 357.1 [M+H⁺]

¹H NMR (400 MHz, CDCl₃) δ ppm 7.28-7.32 (m, 5H) 6.38 (br s, 1H) 4.29 (s,2H) 3.88 (br d, J=12.8 Hz, 1H) 3.78-3.83 (m, 1H) 3.69-3.76 (m, 1H) 3.49(br dd, J=12.6, 4.1 Hz, 1H) 3.04 (dt, J=13.7, 6.8 Hz, 1H) 2.10-2.16 (m,1H) 2.03 (dt, J=7.2, 3.7 Hz, 1H) 1.44 (d, J=6.3 Hz, 6H) 1.31 (dd, J=6.8,2.3 Hz, 6H) 0.97 (t, J=3.3 Hz, 1H)

Example 118(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(7a-methyl-5,6,7,7a-tetrahydropyrrolo[1,2-d][1,2,4]oxadiazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone5-methyl-3,4-dihydro-2H-pyrrole

To a solution of 4-chlorobutanenitrile (1.83 mL, 19.31 mmol) in2-methoxy-2-methyl-propane (20 mL, 23.18 mmol) was addedbromo(methyl)magnesium (2763.65 mg, 23.18 mmol) drop-wise at 0° C. Itwas allowed to reach room temperature. After 15 min, THF (10 mL) wasadded drop-wise over 5 min. H₂O (30 mL) was added and it was extractedwith MTBE (30 mL×2). The combined organic layer was dried over Na₂SO₄and concentrated in vacuum to give the title compound (800 mg, 9.6235mmol, 49.826% yield) as yellow oil. It was directly used in the nextstep.

tert-butyl(1R,5S,6r)-6-(7a-methyl-5,6,7,7a-tetrahydropyrrolo[1,2-d][1,2,4]oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A 100 mL round-bottom flask was charge with tert-butyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(250 mg, 0.9600 mmol), 5-methyl-3,4-dihydro-2H-pyrrole (500 mg, 6.01mmol), triethylamine (0.4 mL, 2.88 mmol) and DMF (12.5 mL). The reactionwas stirred at 20° C. for 16 hr to give a yellow solution. H₂O (30 mL)was added and it was extracted with EtOAc (30 mL×2). The combinedorganic layer was dried over Na₂SO₄ and concentrated in vacuum to givethe title compound (300 mg, 0.9760 mmol, 101.78% yield) as yellow oil.It was directly used in the next step.

LC-MS Method1 0.810 min, MS (m/z) 307.9 (M+H⁺).

3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-7a-methyl-5,6,7,7a-tetrahydropyrrolo[1,2-d][1,2,4]oxadiazoleTFA salt

A 100 mL round-bottom flask was charged with tert-butyl(1R,5S,6r)-6-(7a-methyl-5,6,7,7a-tetrahydropyrrolo[1,2-d][1,2,4]oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(250 mg, 0.8100 mmol), 2,2,2-trifluoroacetic acid (1 mL, 13.06 mmol) andDCM (10 mL). The reaction was stirred at 20° C. for 3 hr to give ayellow solution. The reaction mixture was evaporated in vacuum to givethe title compound (260 mg, 0.8092 mmol, 99.498% yield) as red oil. Itwas directly use in the next step.

(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(7a-methyl-5,6,7,7a-tetrahydropyrrolo[1,2-d][1,2,4]oxadiazol-3-yl-3-azabicyclo[3.1.0]hex-3-yl]methanone

A 100 mL round-bottom flask was charged with5-isopropyl-1H-pyrazole-3-carboxylic acid (130 mg, 0.8400 mmol), HATU(354.6 mg, 0.9300 mmol), N-ethyl-N-isopropylpropan-2-amine (0.58 mL,3.37 mmol) and DMF (6.5 mL). After stirred for 30 min,3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-7a-methyl-5,6,7,7a-tetrahydropyrrolo[1,2-d][1,2,4]oxadiazoleTFA salt (270.93 mg, 0.8400 mmol) was added. The reaction mixture wasstirred at 20° C. for 16 hr to give a yellow solution. H₂O (30 mL) wasadded and it was extracted with EtOAc (30 mL×2). The combined organiclayer was dried over Na₂SO₄ and concentrated in vacuum to give a yellowoil. The crude was purified by Prep-HPLC (NH₃). The afforded flows wereconcentrated in vacuum to remove most of CH₃CN and lyophilized to givethe title compound (32.74 mg, 0.0950 mmol, 11.269% yield) as whitesolid.

LC-MS Method1: 344.1 [M+H⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 6.36 (br s, 1H), 4.20-4.44 (m, 1H), 3.95 (brs, 1H), 3.80 (br s, 1H), 3.45-3.57 (m, 2H), 2.97 (ddd, J=6.32, 9.01,11.44 Hz, 2H), 2.03-2.15 (m, 1H), 1.95 (br s, 1H), 1.85-1.91 (m, 1H),1.80-1.85 (m, 1H), 1.69-1.76 (m, 1H), 1.57-1.66 (m, 1H), 1.35 (s, 3H),1.22 (d, J=6.88 Hz, 6H)

Example 119(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanoneethyl(1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylate

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (1.69 g,10.96 mmol) in DMF (20 mL) were added HATU (5.41 g, 14.24 mmol), DIPEA(5.43 mL, 32.87 mmol) and ethyl(1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate (2.1 g, 10.96 mmol).The mixture was stirred at 15° C. for 4 h to give brown solution. Thereaction mixture was poured into H₂O (100 mL) and extracted with EtOAc(100 mL×3). The combined organic layers were washed with brine (250 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude product was purified by flash column (PE to 40% EtOAc in PE) togive brown solid. The afforded solid was triturated with EtOAc/PE (10mL/20 mL) and dried in air to give the title compound (1.45 g, 4.9768mmol, 45.422% yield) as white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm=10.58 (brs, 1H), 6.47 (s, 1H), 4.35(d, J=11.2 Hz, 1H), 4.20 (d, J=11.2 Hz, 1H), 4.20 (q, J=6.8 Hz, 2H),3.95 (d, J=11.6, 4.0 Hz, 1H), 3.68 (d, J=11.6, 4.0 Hz, 1H), 3.02 (qn,J=3.6 Hz, 1H), 2.30-2.15 (m, 2H), 1.50-1.45 (m, 1H), 1.31 (d, J=6.8 Hz,6H), 1.26 (t, J=6.8 Hz, 3H).

(1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carbohydrazide

To a solution of ethyl(1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylate(450 mg, 1.54 mmol) in EtOH (4 mL) was added hydrazine hydrate (236.69mg, 4.63 mmol). The mixture was stirred at 80° C. for 13 h under N₂ togive white suspension. LCMS showed the desire MS and a part of thestarting material was remained. Then hydrazine hydrate (236.69 mg, 4.63mmol) was added to the mixture. The mixture was stirred at 80° C. for 13h under N₂ to give white suspension. LCMS showed the desire MS and apart of the starting material was remained. Then hydrazine hydrate(236.69 mg, 4.63 mmol) was added to the mixture. The mixture was stirredat 80° C. for 13 h under N₂ to give white suspension. LCMS showed desireMS and a part of the starting material was remained. The reactionmixture was concentrated directly. The afforded solid was trituratedwith PE (15 mL) and dried in air to give the title compound (390 mg,1.4063 mmol, 91.051% yield) as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.96 (brs, 1H), 9.06 (s, 1H), 6.37(brs, 1H), 4.50-3.80 (m, 6H), 3.50-3.40 (m, 1H), 3.00-2.90 (m, 1H),2.05-1.95 (m, 1H), 1.95-1.85 (m, 1H), 1.25 (d, J=7.2 Hz, 6H), 0.90-0.80(m, 1H).

(1R,5S,6r)-N′-acetyl-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carbohydrazide

To a mixture of(1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carbohydrazide(270 mg, 0.9700 mmol) in DCM (10 mL) were added acetic anhydride (119.27mg, 1.17 mmol) and Et₃N (0.34 mL, 1.95 mmol). The reaction mixture wasstirred at 15° C. for 12 h to give white suspension. The suspension wasfiltered. The filter cake was washed with DCM (5 mL×3) and dried invacuo to afford the title compound (250 mg, 0.7828 mmol, 80.404% yield)as white solid.

(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

A solution of(1R,5S,6r)-N′-acetyl-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carbohydrazide(250 mg, 0.7800 mmol) in POCl₃ (5 mL, 69.14 mmol) was stirred at 90° C.for 4 h to give brown mixture. TLC showed one new spot (Rf=0.3) wasdetected. The reaction mixture was concentrated in vacuo to give aresidue. The residue was dissolved with DCM (15 mL). The resultingmixture was washed with NaHCO₃ (eq., 15 mL×2). The aqueous phase wasextracted with DCM (10 mL×3). The combined organic phase was dried withanhydrous Na₂SO₄, filtered and concentrated in vacuum to give a residue.The residue was purified by prep-TLC (SiO₂, DCM:MeOH=10:1) andlyophilized to afford the title compound (120 mg, 0.3799 mmol, 48.535%yield) as yellow powder.

LC-MS Method1: 301.9 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.99-10.47 (m, 1H), 6.53 (s, 1H),4.45 (br d, J=10.6 Hz, 1H), 4.29 (d, J=12.8 Hz, 1H), 3.99 (dd, J=11.6,4.0 Hz, 1H), 3.72 (dd, J=12.7, 4.1 Hz, 1H), 2.99-3.09 (m, 1H), 2.49 (s,3H), 2.35-2.43 (m, 1H), 2.26-2.34 (m, 1H), 1.96 (t, J=3.4 Hz, 1H), 1.31(d, J=6.9 Hz, 6H)

Example 120(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(4-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanoneN′-({(1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hex-6-yl}carbonyl)-N,N-dimethylhydrazonoformamide

To a solution of(1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carbohydrazide(390 mg, 1.41 mmol) in DMF (4 mL) was added1,1-dimethoxy-N,N-dimethylmethanamine (0.2 mL, 1.48 mmol). The mixturewas stirred at 100° C. for 15 h to give yellow solution. The reactionmixture was concentrated directly to give the title compound (450 mg,1.3538 mmol, 96.265% yield) as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.94 (brs, 1H), 10.10 (s, 1H), 7.66 (s,1H), 6.36 (brs, 1H), 4.40-4.30 (m, 1H), 4.00-3.70 (m, 2H), 3.50-3.40 (m,1H), 3.00-2.90 (m, 1H), 2.80-2.75 (m, 1H), 2.76 (s, 6H), 2.00-1.80 (m,2H), 1.21 (d, J=7.2 Hz, 6H), 1.25-1.20 (m, 1H).

(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(4-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution ofN′-({(1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hex-6-yl}carbonyl)-N,N-dimethylhydrazonoformamide(200 mg, 0.6000 mmol) in THF (4 mL) was added methanamine (0.49 mL,12.03 mmol). Then HOAc (2 mL, 0.6000 mmol) was added to the mixture at0° C. The mixture was stirred at 100° C. to give colorless solution. Thereaction mixture was concentrated directly. The residue was purified byprep-HPLC (HCl) to give the title compound (37.05 mg, 0.1234 mmol,20.501% yield) as white solid.

¹H NMR (400 MHz, DMSO-d6) δ ppm 9.39 (br s, 1H), 6.42 (s, 1H), 4.46 (brd, J=11.88 Hz, 1H), 4.10 (br d, J=12.51 Hz, 1H), 3.95 (br dd, J=12.01,3.88 Hz, 1H), 3.85 (s, 3H), 3.60 (br dd, J=12.44, 4.06 Hz, 1H), 2.97(spt, J=6.90 Hz, 1H), 2.47 (br s, 2H), 2.16 (t, J=3.25 Hz, 1H), 1.22 (d,J=6.75 Hz, 6H)

Example 121(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(4-phenyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(4-phenyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of(1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carbohydrazidein MeCN (2 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (21.52mg, 0.1800 mmol). The mixture was stirred at 50° C. for 30 min. Thenaniline (0.03 mL, 0.3600 mmol) was added to the mixture, followed byAcOH (2 mL). The mixture was stirred at 120° C. for 5 h to givecolorless solution. The residue was purified by prep-HPLC (HCl). Theafforded flows were combined, concentrated to remove most of CH₃CN andlyophilized to give the title compound (24.12 mg, 0.0666 mmol, 36.912%yield) as white solid.

LC-MS Method1: 362.9 [M+H⁺]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.28-9.55 (1H, m), 7.58-7.70 (5H, m),6.34 (1H, s), 4.26 (1H, br d, J=12.01 Hz), 3.81-3.92 (2H, m), 3.54 (1H,dd, J=12.44, 4.19 Hz), 2.93 (1H, dt, J=13.85, 6.89 Hz), 2.54-2.58 (1H,m), 2.39 (1H, dt, J=7.19, 3.66 Hz), 1.68 (1H, t, J=3.31 Hz), 1.19 (6H,d, J=7.00 Hz)

Example 122{(1R,5S,6r)-6-[4-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanone{(1R,5S,6r)-6-[4-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of(1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carbohydrazidein MeCN (2 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (47.96mg, 0.3600 mmol). The mixture was stirred at 80° C. for 30 min. Then4-fluoroaniline (0.07 mL, 0.7200 mmol) and AcOH (216.36 mg, 3.61 mmol)were added. The mixture was stirred at 90° C. for 5 h to give colorlesssolution. The reaction mixture was concentrated directly. The residuewas purified by prep-HPLC (HCl) to give the title compound (5.67 mg,0.0149 mmol, 4.1333% yield) as gray solid.

LC-MS Method1: 381.0 [M+H⁺]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.92 (1H, br s), 8.67 (1H, s), 7.62(2H, br dd, J=8.91, 4.89 Hz), 7.35-7.51 (2H, m), 6.33 (1H, s), 4.28 (1H,br d, J=12.05 Hz), 3.80-3.94 (2H, m), 3.52 (1H, br d, J=8.03 Hz),2.85-3.01 (1H, m), 2.19 (1H, br s), 1.92-2.04 (1H, m), 1.51 (1H, br s),1.13-1.27 (6H, m)

Example 123[(1R,5S,6r)-6-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone[(1R,5S,6r)-6-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(30 mg, 0.1000 mmol) in xylene (2 mL, 0.1000 mmol) were addedmethylamine (0.74 mL, 1.99 mmol) and TsOH (1.71 mg, 0.0100 mmol). Themixture was stirred at 140° C. for 12 h to give brown solution. Thereaction mixture was concentrated directly. The residue was purified byprep-HPLC (HCl). The afforded flows were combined, concentrated toremove most of CH₃CN and lyophilized to give the title compound (11.82mg, 0.0376 mmol, 37.765% yield) as light yellow solid.

LC-MS Method1: 314.9 [M+H⁺]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.41 (1H, s), 4.44 (1H, br d, J=11.80Hz), 4.09 (1H, d, J=12.30 Hz), 3.94 (1H, br dd, J=11.92, 4.14 Hz), 3.71(3H, s), 3.59 (1H, br dd, J=12.55, 4.27 Hz), 2.96 (1H, dt, J=13.80, 6.90Hz), 2.56 (3H, s), 2.38 (1H, br d, J=3.76 Hz), 2.29-2.35 (1H, m), 2.28(1H, s), 2.14 (1H, t, J=3.39 Hz), 1.21 (6H, dd, J=7.03, 1.00 Hz)

Example 124[(1R,5S,6r)-6-(4-cyclobutyl-5-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone[(1R,5S,6r)-6-(4-cyclobutyl-5-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

To a mixture of(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(30 mg, 0.1000 mmol) in o-Xylene (1 mL) were added TsOH (0.17 mg, 0mmol) and cyclobutanamine (0.02 mL, 0.2000 mmol). The reaction mixturewas stirred at 140° C. for 16 h to give brown mixture. The reactionmixture was concentrated in vacuo to give a residue. The residue waspurified by prep-HPLC (HCl). The afforded flows were combined,concentrated to remove most of CH₃CN and lyophilized to afford the titlecompound (10.71 mg, 0.0302 mmol, 30.351% yield) as yellow solid.

LC-MS Method1: 355.0 [M+H⁺]

¹H NMR (400 MHz, DMSO-d6) δ ppm 6.42 (s, 1H), 4.85-4.98 (m, 1H), 4.45(br d, J=12.0 Hz, 1H), 4.05 (d, J=12.3 Hz, 1H), 3.93 (br dd, J=11.9, 4.1Hz, 2H), 3.61 (br s, 1H), 3.58 (br s, 1H), 2.91-3.01 (m, 1H), 2.63-2.69(m, 2H), 2.60 (s, 3H), 2.42-2.45 (m, 1H), 2.36 (br d, J=3.8 Hz, 1H),2.04 (t, J=3.4 Hz, 1H), 1.84 (td, J=10.2, 5.0 Hz, 2H), 1.22 (d, J=7.0Hz, 6H)

Example 125[(1R,5S,6r)-6-(4-cyclohexyl-5-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanonetert-butyl(1R,5S,6r)-6-(cyclohexylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (500 mg, 2.2 mmol) in DMF (6 mL) were added HATU (1086.86 mg, 2.86mmol), cyclohexanamine (0.28 mL, 2.42 mmol) and Et₃N (0.91 mL, 5.5mmol). The mixture was stirred at 20° C. for 12 h to give graysuspension. TLC (PE:EtOAc=1:1) showed the reaction was completed. Thereaction mixture was poured into H₂O (15 mL) and filtered. The filtercake was washed with H₂O (15 mL×2) and dried in air to give the titlecompound (650 mg, 2.1075 mmol, 95.791% yield) as white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.48 (d, J=8.0 Hz, 1H), 3.85-3.70(m, 1H), 3.67 (d, J=11.2 Hz, 1H), 3.59 (d, J=11.2 Hz, 1H), 3.45-3.35 (m,2H), 2.04 (brs, 2H), 1.91 (brd, J=9.6 Hz, 2H), 1.80-1.70 (m, 2H),1.65-1.55 (m, 1H), 1.44 (s, 9H), 1.50-1.20 (m, 2H), 1.25-1.05 (m, 4H).

tert-butyl(1R,5S,6r)-6-(cyclohexylcarbamothioyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-(cyclohexylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(600 mg, 1.95 mmol) in THF (6 mL) was added2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide(802.59 mg, 1.98 mmol). The mixture was stirred at 20° C. for 12 h togive brown solution. TLC (PE:EtOAc=5:1) showed a new spot. The reactionmixture was poured into H₂O (20 mL) and extracted with EtOAc (20 mL×4).The combined organic layers were washed with brine (50 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by flash column (PE to 10% EtOAc in PE) to give thetitle compound (350 mg, 1.0786 mmol, 55.446% yield) as gray solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (brd, J=7.2 Hz, 1H), 4.50-4.35(m, 1H), 3.65 (d, J=11.2 Hz, 1H), 3.57 (d, J=11.2 Hz, 1H), 3.50-3.40 (m,2H), 2.45-2.35 (m, 2H), 2.15-2.05 (m, 2H), 1.80-1.50 (m, 4H), 1.45 (s,9H), 1.50-1.40 (m, 2H), 1.30-1.10 (m, 4H).

tert-butyl(1R,5S,6r)-6-[(Z)-(cyclohexylimino)(methylthio)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-(cyclohexylcarbamothioyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(300 mg, 0.9200 mmol), 1-methyl-4-(methylsulfonyl)benzene (0.12 mL,0.9300 mmol) in DMF (6 mL) was added tert-butoxypotassium (124.49 mg,1.11 mmol). The mixture was stirred at 20° C. for 9 h to give yellowsolution. The reaction mixture was poured into H₂O (20 mL) and extractedwith EtOAc (20 mL×4). The combined organic layers were washed with brine(50 mL×2), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the title compound (300 mg, 0.8862 mmol, 95.855% yield)as a light yellow solid.

LC-MS Method1 0.693 min, MS (m/z) 339.0 (M+H⁺).

tert-butyl(1R,5S,6r)-6-(4-cyclohexyl-5-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(Z)-(cyclohexylimino)(methylthio)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(300 mg, 0.8900 mmol) and acetohydrazide (98.48 mg, 1.33 mmol) in THF (5mL) was added 2,2,2-trifluoroacetic acid (0.03 mL, 0.4400 mmol). Themixture was stirred at 75° C. for 16 h to give colorless solution. Thereaction mixture was poured into H₂O (20 mL) and extracted with EtOAc(20 mL×4). The combined organic layers were washed with brine (50 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude product was purified by flash column (EtOAc/MeOH=I/O to 5/1) togive the title compound (280 mg, 0.8082 mmol, 91.189% yield) ascolorless gum.

LC-MS Method1 0.718 min, MS (m/z) 347.1 (M+H⁺).

(1R,5S,6r)-6-(4-cyclohexyl-5-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride

A solution of tert-butyl(1R,5S,6r)-6-(4-cyclohexyl-5-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(130 mg, 0.3800 mmol) in HCl/dioxane (0.09 mL, 0.3800 mmol) was stirredat 20° C. for 30 min to give colorless solution. LCMS showed the desireMS and the starting material was consumed up. The reaction mixture wasconcentrated directly to give the title compound (100 mg, 0.3536 mmol,94.238% yield) as yellow gum.

[(1R,5S,6r)-6-(4-cyclohexyl-5-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (65.42 mg,0.4200 mmol) in DMF (1.7422 mL) were added HATU (188.11 mg, 0.5000mmol), Et₃N (0.18 mL, 1.06 mmol) and(1R,5S,6r)-6-(4-cyclohexyl-5-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (100 mg, 0.3500 mmol). The mixture was stirred at 20° C.for 12 h to give yellow solution. LCMS showed the desire MS and thestarting material was consumed up. The reaction mixture was poured intoH₂O (20 mL) and extracted with EtOAc (20 mL×4). The combined organiclayers were washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (HCl). The afforded flows were combined, concentrated toremove most of CH₃CN and lyophilized to give yellow solid(crude). Theresidue was purified by prep-TLC (EtOAc) and lyophilized to give thetitle compound as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.84-11.67 (1H, m), 6.53 (1H, s),4.46 (1H, br d, J=10.76 Hz), 4.26 (1H, br d, J=12.76 Hz), 3.96-4.12 (2H,m), 3.76 (1H, br dd, J=12.88, 4.25 Hz), 3.02-3.18 (1H, m), 2.74 (1H, brs), 2.51 (3H, br s), 2.11 (1H, br s), 1.89-2.00 (5H, m), 1.79 (1H, br d,J=13.76 Hz), 1.67-1.75 (2H, m), 1.38-1.50 (2H, m), 1.33 (6H, dd, J=6.88,1.63 Hz), 1.25 (1H, br d, J=6.38 Hz)

Example 126(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(30 mg, 0.1000 mmol) in o-Xylene (1 mL) were added aniline (0.02 mL,0.2000 mmol) and TsOH (0.17 mg, 0 mmol). The reaction mixture wasstirred at 140° C. for 16 h to give brown mixture. The reaction mixturewas concentrated in vacuo to give a residue. The residue was purified byprep-HPLC (HCl). The afforded flows were combined, concentrated toremove most of CH₃CN and lyophilized to afford the title compound (18.55mg, 0.0493 mmol, 49.496% yield) as white powder.

LC-MS Method1: 377.0 [M+H⁺]

¹H NMR (400 MHz, DMSO-d6) δ ppm 7.54-7.79 (m, 5H), 6.32 (s, 1H), 4.17(br d, J=12.0 Hz, 1H), 3.85 (br dd, J=11.8, 4.1 Hz, 2H), 3.74 (br d,J=12.4 Hz, 2H), 2.93 (dt, J=13.9, 7.1 Hz, 1H), 2.68 (br d, J=1.8 Hz,1H), 2.35 (s, 3H), 2.28 (dt, J=7.5, 3.6 Hz, 1H), 1.45 (t, J=3.3 Hz, 1H),1.19 (d, J=6.9 Hz, 6H)

Example 127{(1R,5S,6r)-6-[4-(4-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanone{(1R,5S,6r)-6-[4-(4-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(25 mg, 0.0800 mmol) in p-Xylene (0.50 mL) were added 4-fluoroaniline(0.02 mL, 0.1700 mmol) and TsOH (0.14 mg, Ommol). The mixture wasstirred at 140° C. for 12 h to give brown solution. The reaction mixturewas concentrated directly. The residue was purified by prep-HPLC (HCl).The afforded flows were combined, concentrated to remove most of CH₃CNand lyophilized to give the title compound (13.91 mg, 0.0353 mmol,42.506% yield) as white solid.

LC-MS Method1: 395.0 [M+H⁺]

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.76 (1H, dd, J=8.69, 4.82 Hz),7.73-7.80 (1H, m), 7.55 (2H, t, J=8.63 Hz), 6.30-6.37 (1H, m), 4.18 (1H,br d, J=12.01 Hz), 3.86 (1H, br dd, J=11.94, 4.06 Hz), 3.75 (1H, br d,J=12.51 Hz), 3.51 (1H, br dd, J=12.44, 4.06 Hz), 2.88-2.99 (1H, m), 2.39(3H, s), 2.31-2.37 (1H, m), 1.53 (1H, t, J=3.25 Hz), 1.19 (6H, d, J=7.00Hz)

Example 128(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[5-methyl-4-(4-methylphenyl)-4H-1,2,4-triazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[5-methyl-4-(4-methylphenyl)-4H-1,2,4-triazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone

To a mixture of(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(20 mg, 0.0700 mmol) in o-Xylene (1 mL) were added p-toluidine (0.01 mL,0.1300 mmol) and TsOH (0.11 mg, 0 mmol). The reaction mixture wasstirred at 140° C. for 12 h to give brown mixture. The reaction mixturewas concentrated in vacuo to give a residue. The residue was purified byprep-HPLC (HCl). The afforded flows were combined, concentrated toremove most of CH₃CN and lyophilized to afford the title compound (11.42mg, 0.0278 mmol, 41.954% yield) as yellow solid.

LC-MS Method1: 391.0 [M+H⁺]

¹H NMR (400 MHz, DMSO-d6) δ ppm 7.49-7.53 (m, 2H), 7.45-7.49 (m, 2H),6.33 (s, 1H), 4.20 (br d, J=12.1 Hz, 1H), 3.86 (br dd, J=12.0, 4.3 Hz,2H), 3.75 (br d, J=12.4 Hz, 1H), 2.93 (dt, J=13.9, 6.9 Hz, 1H), 2.46 (brd, J=3.1 Hz, 1H), 2.41 (s, 3H), 2.34 (s, 3H), 2.29 (dt, J=7.4, 3.8 Hz,1H), 1.46 (t, J=3.4 Hz, 1H), 1.19 (d, J=6.9 Hz, 6H)

Example 129{(1R,5S,6r)-6-[4-(4-ethylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanone{(1R,5S,6r)-6-[4-(4-ethylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(5-isopropyl-1H-pyrazol-3-yl)methanone

To a mixture of(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(20 mg, 0.0700 mmol) in o-Xylene (0.9535 mL) were added 4-ethylaniline(0.02 mL, 0.1300 mmol) and TsOH (0.11 mg, 0 mmol).

The reaction mixture was stirred at 140° C. for 12 h to give brownmixture. LCMS showed the starting material was consumed completely. Thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (HCl). The afforded flows werecombined, concentrated to remove most of CH₃CN and lyophilized to affordthe title compound (9.41 mg, 0.0229 mmol, 34.521% yield) as whitepowder.

LC-MS Method1: 405.0 [M+H⁺]

¹H NMR (400 MHz, DMSO-d6) δ ppm 7.47-7.57 (m, 4H), 6.25-6.40 (m, 1H),4.18 (br d, J=11.9 Hz, 1H), 3.86 (br dd, J=11.9, 4.1 Hz, 2H), 3.75 (brd, J=12.5 Hz, 1H), 3.49 (br s, 2H), 2.87-2.97 (m, 1H), 2.66-2.76 (m,2H), 2.36 (s, 3H), 2.28-2.33 (m, 2H), 1.46 (t, J=3.3 Hz, 1H), 1.16-1.25(m, 9H)

Example 130(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(6-methyl[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonetert-butyl(1R,5S,6r)-6-{[2-(5-methyl-2-pyridinyl)hydrazino]carbonyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (300 mg, 1.32 mmol) in DMF (5 mL) were added2-hydrazino-5-methylpyridine (162.58 mg, 1.32 mmol), Et₃N (0.24 mL, 1.45mmol) and HATU (551.79 mg, 1.45 mmol). The reaction mixture was stirredat 15° C. for 16 h to give brown mixture. The reaction mixture wasconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (SiO₂, PE/EA=6/1) to give the title compound (330mg, 0.9928 mmol, 75.206% yield) as yellow solid.

LC-MS Method1 0.639 min, MS (m/z) 332.9 (M+H⁺).

tert-butyl(1R,5S,6r)-6-(6-methyl[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of tert-butyl(1R,5S,6r)-6-{[2-(5-methyl-2-pyridinyl)hydrazino]carbonyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate(270 mg, 0.8100 mmol) in MeCN (5 mL) was added Burgess reagent (387.13mg, 1.62 mmol). The reaction mixture was stirred at 90° C. for 12 h. TLCshowed the starting material was consumed completely, and one new spotwas detected. The reaction mixture was concentrated in vacuo to give aresidue. The residue was purified by prep-TLC (SiO₂, DCM:MeOH=10:1) toafford the title compound (130 mg, 0.4135 mmol, 50.908% yield) as yellowsolid.

LC-MS Method1 0.693 min, MS (m/z) 314.9 (M+H⁺).

3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-6-methyl[1,2,4]triazolo[4,3-a]pyridineTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-(6-methyl[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(130 mg, 0.4100 mmol) in DCM (4 mL) was added TFA (1 mL, 13.46 mmol).The reaction mixture was stirred at 15° C. for 2 h to give yellowmixture. TLC (DCM:MeOH=10:1) showed the starting material was consumedcompletely. The reaction mixture was concentrated in vacuo to give thetitle compound (135 mg, 0.4112 mmol, 99.446% yield) as yellow oil.

(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(6-methyl[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-6-methyl[1,2,4]triazolo[4,3-a]pyridineTFA salt (130 mg, 0.4000 mmol) in DMF (3.0297 mL) were added5-isopropyl-1H-pyrazole-3-carboxylic acid (61.05 mg, 0.4000 mmol), DIPEA(0.2 mL, 1.19 mmol) and HATU (180.57 mg, 0.4800 mmol). The reactionmixture was stirred at 15° C. for 12 h to give brown mixture. LCMSshowed the starting material was consumed completely. The reactionmixture was purified by prep-HPLC (HCl). The afforded flows werecombined, concentrated to remove most of CH₃CN and lyophilized to affordthe title compound (25.34 mg, 0.0698 mmol, 17.624% yield) as whitesolid.

LC-MS Method1: 350.9 [M+H⁺]

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (dd, J=6.9, 1.2 Hz, 6H), 2.37 (d,J=3.6 Hz, 1H), 2.40 (s, 3H), 2.44 (br d, J=1.9 Hz, 1H), 2.47 (dd, J=3.4,1.6 Hz, 1H), 2.93-3.03 (m, 1H), 3.62 (br s, 1H), 3.66 (br d, J=3.5 Hz,1H), 4.00 (br dd, J=11.9, 4.2 Hz, 1H), 4.21 (d, J=12.4 Hz, 1H), 4.53 (brd, J=11.8 Hz, 1H), 6.45 (s, 1H), 7.78 (d, J=9.5 Hz, 1H), 7.91 (d, J=9.3Hz, 1H), 8.86 (s, 1H).

Example 131(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(6-methoxy[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone2-hydrazino-5-methoxypyridine

2-chloro-5-methoxypyridine (1.5.g, 7.98 mmol) and hydrazine hydrate(20.g, 379.54 mmol) was combined and heated slowly to 140° C. Thereaction mixture was stirred at 140° C. for 16 hours. LCMS showed thedesired peak was found. The mixture was concentrated under reducedpressure to afford a residue. The residue was purified by Combi Flashwith silica gel (MeOH/DCM=1/10) to give the title compound (650 mg,4.6709 mmol, 58.548% yield) as yellow oil.

LC-MS Method1 0.192 min, MS (m/z) 140.0 (M+H⁺).

tert-butyl(1R,5S,6r)-6-{[2-(5-methoxy-2-pyridinyl)hydrazino]carbonyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a mixture of(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (979.85 mg, 4.31 mmol) and HATU (2.46 g, 6.47 mmol) in DCM (20 mL)was added Et₃N (1.43 mL, 8.62 mmol), and the resulting mixture wasstirred at 20° C. for 10 min. Then 2-hydrazino-5-methoxypyridine (600mg, 4.31 mmol) was added. The resulting mixture was stirred at 20° C.under N₂ for 16 hours to give brown mixture. The reaction mixture wasdiluted with H₂O (20 mL) and extracted with EtOAc (30 ml×3). The organiclayer was washed with brine (20 mL), dried over Na₂SO₄ and concentratedin vacuum to give brown oil. The crude oil was purified by prep-TLC(PE/EA=1/1) to give the title compound (400 mg, 1.1481 mmol, 26.628%yield) as yellow solid.

LC-MS Method1: 349.1 [M+H⁺]. tert-butyl(1R,5S,6r)-6-(6-methoxy[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-{[2-(5-methoxy-2-pyridinyl)hydrazino]carbonyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate(380 mg, 1.09 mmol) in MeCN (20 mL) was added Burgess reagent (649.78mg, 2.73 mmol). The mixture was stirred at 95° C. under N₂ for 16 hours.The reaction mixture was diluted with H₂O (20 mL) and extracted withEtOAc (30 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by Combi Flash with silica gel (EtOAc/PE=1/1) togive the title compound (120 mg, 0.3133 mmol, 28.723% yield) as yellowsolid.

LC-MS Method1: 331.0 [M+H+].3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-6-methoxy[1,2,4]triazolo[4,3-a]pyridineTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-(6-methoxy[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(100 mg, 0.30 mmol) in DCM (3 mL) was added TFA (0.13 mL, 1.82 mmol) at20° C. The mixture was stirred at 20° C. for 16 hours. The reactionmixture was concentrated to give the title compound (100 mg, 0.4343mmol, 143.48% yield) as yellow oil.

LC-MS Method1: 230.95 [M+H⁺].(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(6-methoxy[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a mixture of 5-isopropyl-1H-pyrazole-3-carboxylic acid (65 mg, 0.42mmol) in DCM (3 mL) were added HATU (241.77 mg, 0.6300 mmol) and Et₃N(0.14 mL, 0.8400 mmol), and the mixture was stirred at 20° C. for 10 minunder N₂. Then,3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-6-methoxy[1,2,4]triazolo[4,3-a]pyridineTFA salt (97.08 mg, 0.4200 mmol) in DCM (2 mL) was added. The resultingmixture was stirred at 20° C. for 16 hr to give brown mixture. Thereaction was diluted with H₂O (20 mL) and extracted with DCM (20 mL).The combined organic layers were separated, then dried over Na₂SO₄ andconcentrated in vacuum to give brown oil. The brown oil was purified byprep-HPLC (FA) and the afforded flows were lyophilized to afford thetitle compound (40.47 mg, 0.1054 mmol, 24.997% yield) as pale yellowsolid.

LC-MS Method1: 367.0 [M+H⁺].

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.11 (s, 1H), 7.65 (d, J=10.0 Hz, 1H),7.39 (s, 1H), 7.06 (dd, J=2.0, 10.0 Hz, 1H), 6.57 (s, 1H), 4.55 (d,J=11.5 Hz, 1H), 4.44 (d, J=12.5 Hz, 1H), 4.10 (dd, J=3.8, 11.8 Hz, 1H),3.89 (s, 3H), 3.84-3.73 (m, 1H), 3.07 (td, J=7.2, 13.8 Hz, 1H),2.82-2.74 (m, 1H), 2.31-2.29 (m, 1H), 1.89 (br s, 1H), 1.33 (d, J=6.8Hz, 6H)

Example 132(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-([1,2,3]triazolo[1,5-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-([1,2,3]triazolo[1,5-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (25.64 mg,0.1700 mmol) in DMF (1.2489 mL) were added HATU (47.82 mg, 0.2500 mmol)and DIPEA (64.5 mg, 0.50 mmol). The reaction mixture was stirred at 15°C. for 30 min. Then3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-1[1,2,3]triazolo[1,5-a]pyridineTFA salt (33.3 mg, 0.1700 mmol) was added. The reaction mixture wasstirred at 15° C. for 0.5 hr to give a yellow mixture. LCMS showed thedesired MS. The reaction mixture was purified by prep-HPLC (NH₃) to givethe title compound (18.6 mg, 0.0553 mmol, 33.249% yield) as whitepowder.

LC-MS Method1: 336.9 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.64 (d, J=7.2 Hz, 1H), 7.67 (d, J=8.8Hz, 1H), 7.19 (dd, J=6.8, 8.3 Hz, 1H), 6.94 (dt, J=1.0, 6.9 Hz, 1H),6.52 (s, 1H), 4.42 (br d, J=11.3 Hz, 1H), 4.35 (d, J=12.8 Hz, 1H), 4.05(dd, J=4.4, 11.1 Hz, 1H), 3.77 (dd, J=4.4, 12.6 Hz, 1H), 3.09-2.98 (m,1H), 2.49 (td, J=3.8, 7.4 Hz, 1H), 2.30 (td, J=3.8, 7.4 Hz, 1H), 1.96(t, J=3.4 Hz, 1H), 1.31 (d, J=6.8 Hz, 6H).

Example 133(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl[1,2,3]triazolo[1,5-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonebromo(4-methyl-2-pyridinyl)magnesium

To a solution of 2-bromo-4-methylpyridine (0.67 mL, 6.33 mmol) in THF(10 mL) was added chloro(isopropyl)magnesium (3.2 mL, 6.33 mmol) at 15°C. The reaction mixture was stirred at 0° C. for 4 hr to give the titlecompound as a mixture. The reaction mixture was used for the next stepwithout further purification.

tert-butyl(1R,5S,6r)-6-[hydroxy(4-methyl-2-pyridinyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (300 mg,1.42 mmol) in THF (3 mL) was added bromo(4-methyl-2-pyridinyl)magnesium(418.2 mg, 2.13 mmol) at 0° C. The reaction mixture was stirred at 0° C.for 2 hr to give a light yellow mixture. TLC (EA) showed a new spot. Thereaction mixture was quenched with H₂O (30 mL) and extracted with EtAOc(30 mL×2). The organic layer was washed with brine (30 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by silica gel column (PE/EA=1:0to 1:2) to give the title compound (400 mg, 1.3141 mmol, 92.542% yield)as light yellow gum.

¹H NMR (400 MHz, DMSO-d₆) δ=8.31 (d, J=5.2 Hz, 1H), 7.30 (s, 1H), 7.08(d, J=5.2 Hz, 1H), 5.36 (d, J=4.8 Hz, 1H), 4.50-4.40 (m, 1H), 3.45-3.35(m, 4H), 2.32 (s, 3H), 1.65-1.50 (m, 2H), 1.34 (s, 9H), 0.85-0.80 (m,1H).

tert-butyl(1R,5S,6r)-6-[(4-methyl-2-pyridinyl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[hydroxy(4-methyl-2-pyridinyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(300 mg, 0.9900 mmol) in DCM (6 mL) was added DMP (418.04 mg, 0.9900mmol) at 15° C. The reaction mixture was stirred at 15° C. for 20 min togive a white mixture. TLC (PE/EA=1:1) showed a new spot. The combinedreaction mixture was quenched with NaHCO₃ (30 mL) and extracted withEtOAc (30 mL×2). The organic layer was washed with brine (30 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give a crude product as light yellow solid. The crudeproduct was purified by silica column (PE/EA=1:1) to give the titlecompound (300 mg, 0.9922 mmol, 100.66% yield) as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ=8.60 (d, J=4.8 Hz, 1H), 7.76 (s, 1H), 7.51(d, J=4.8 Hz, 1H), 4.50-4.40 (m, 1H), 3.57 (d, J=11.2 Hz, 2H), 3.45-3.35(m, 2H), 3.25-3.20 (m, 1H), 2.40 (s, 3H), 2.20 (brs, 2H), 1.40 (s, 9H).

tert-butyl(1R,5S,6r)-6-(5-methyl[1,2,3]triazolo[1,5-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of tert-butyl(1R,5S,6r)-6-[(4-methyl-2-pyridinyl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(150 mg, 0.5000 mmol) in EtOH (3 mL) was added hydrazine hydrate (37.25mg, 0.7400 mmol). The reaction mixture was stirred at 60° C. for 6 hr togive a colorless mixture. Then copper acetate (4.94 mg, 0.0200 mmol) andethyl acetate (14.304 mL) were added. Then the reaction mixture wasstirred at 20° C. for 1 hr to give a colorless mixture. The reactionmixture was concentrated to give a residue. The residue was purified byperp-TLC (PE/EA=1:1) to give the title compound (50 mg, 0.1590 mmol,32.06% yield) as colorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.51 (d, J=7.2 Hz, 1H), 7.43 (s, 1H),6.75 (dd, J=7.2, 1.6 Hz, 1H), 3.84 (d, J=11.2 Hz, 1H), 3.75 (d, J=11.2Hz, 1H), 3.45-3.35 (m, 2H), 2.43 (s, 3H), 2.35-2.35 (m, 1H), 2.20-2.10(m, 1H), 1.95-1.90 (m, 1H), 1.48 (s, 9H).

3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-5-methyl[1,2,3]triazolo[1,5-a]pyridineTFA salt

To a solution of tert-butyl(1R,5S,6r)-6-(5-methyl[1,2,3]triazolo[1,5-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylatein DCM (5 mL) was added TFA (0.01 mL, 0.1600 mmol). The reaction mixturewas stirred at 20° C. for 16 hr to give a colorless mixture. LCMS showedthe desired MS. The solvent was removed from the reaction mixture togive the title compound. The product was used for the next stepdirectly.

LC-MS Method1 0.398 min, MS (m/z) 214.9 (M+H⁺).

(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl[1,2,3]triazolo[1,5-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (24.46 mg,0.1600 mmol) in DMF (1.1917 mL) was added HATU (45.63 mg, 0.2400 mmol).The reaction mixture was stirred at 15° C. for 30 min. Then3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-5-methyl[1,2,3]triazolo[1,5-a]pyridineTFA salt (34 mg, 0.1600 mmol) and DIPEA (61.52 mg, 0.476 mmol) wereadded. The reaction mixture was stirred at 15° C. for 0.5 hr to give ayellow mixture. LCMS showed the desired MS. The reaction mixture waspurified by prep-HPLC (NH₃) to give the title compound (22.4 mg, 0.0639mmol, 40.285% yield) as white powder.

LC-MS Method1: 350.9 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=8.52 (d, J=7.2 Hz, 1H), 7.41 (s, 1),6.76 (dd, J=1.6, 7.2 Hz, 1H), 6.51 (s, 1H), 4.40 (br d, J=10.8 Hz, 1H),4.34 (d, J=12.4 Hz, 1H), 4.03 (dd, J=4.4, 11.2 Hz, 1H), 3.76 (dd, J=4.4,12.4 Hz, 1H), 3.04 (spt, J=6.9 Hz, 1H), 2.47-2.44 (m, 1H), 2.42 (s, 3H),2.26 (td, J=3.8, 7.4 Hz, 1H), 1.91 (t, J=3.4 Hz, 1), 1.31 (d, J=7.2 Hz,6H)

Example 134(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (90 mg,0.5800 mmol) in DMF (6 mL) were added N-ethyl-N-isopropylpropan-2-amine(0.4 mL, 2.34 mmol) and HATU (266.2 mg, 0.7000 mmol). After stirred for30 min, (1R,5S,6r)-6-(1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexane TFAsalt (79.42 mg, 0.5300 mmol) was added and the reaction mixture wasstirred at 15° C. for 16 hr to give a red solution. H₂O (30 mL) wasadded and it was extracted with EtOAc (30 mL×2). The combined organiclayer was dried over Na₂SO₄ and concentrated in vacuum to give yellowoil. The crude was purified by prep-HPLC (FA) to give the title compound(13.3 mg, 0.0463 mmol, 7.9295% yield) as white solid.

LC-MS Method1: 288.0 [M+H⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 6.41 (s, 1H), 4.42 (br d, J=12.05 Hz, 1H),4.05 (d, J=12.30 Hz, 1H), 3.90 (dd, J=3.89, 11.92 Hz, 1H), 3.57 (br dd,J=4.02, 12.30 Hz, 1H), 2.96 (td, J=6.96, 13.68 Hz, 1H), 2.26-2.35 (m,1H), 2.21 (m, 1H), 1.97 (t, J=3.26 Hz, 1H), 1.22 (d, J=7.03 Hz, 7H)

Example 135(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(1-phenyl-1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanonetert-butyl(1R,5S,6r)-6-(phenylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

A solution of(1R,5S,6r)-3-{[(tert-butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (500 mg, 2.2 mmol), HOBt (356.74 mg, 2.64 mmol), aniline (0.45 mL,2.64 mmol) and EDCI (506.12 mg, 2.64 mmol) in DCM (5 mL) was stirred at10° C. for 30 min. Then it was cooled to 0° C. and aniline (0.3 mL, 3.3mmol) was added drop-wise to be stirred for 16 hr to give a whitesuspension. TLC (DCM/MeOH=10/1 Rf=0.1) showed a new spot was detected.H₂O (10 mL) was added and it was extracted with EtOAc (10 mL×2). Thecombined organic layer was dried over Na₂SO₄ and concentrated in vacuumto give a white solid. The crude was purified by silica gelchromatography (PE/EA=10/1 to 3/1) to give the title compound (590 mg,1.9513 mmol, 88.688% yield) as white solid.

LC-MS Method1 0.858 min, MS (m/z) 303.0 (M+H⁺).

(1R,5S,6r)-N-phenyl-3-azabicyclo[3.1.0]hexane-6-carboxamidehydrochloride

A solution of tert-butyl(1R,5S,6r)-6-(phenylcarbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(640 mg, 2.12 mmol) in HCl/dionane (6 mL, 2.12 mmol) was stirred at 10°C. for 3 hr to give a yellow solution. The reaction mixture wasevaporated in vacuum to give the title compound (500 mg, 2.0946 mmol,98.96% yield) as white solid.

LC-MS Method1 0.285 min, MS (m/z) 203.0 (M+H⁺).

(1R,5S,6r)-3-benzyl-N-phenyl-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a solution of(1R,5S,6r)-N-phenyl-3-azabicyclo[3.1.0]hexane-6-carboxamidehydrochloride (500 mg, 2.09 mmol) and benzaldehyde (0.25 mL, 2.51 mmol)in DCM (15 mL) and MeOH (5 mL) was added triethylamine (0.29 mL, 2.09mmol). After stirring for 5 min, sodium triacetoxyhydroborate (887.86mg, 4.19 mmol) was added. The reaction mixture was stirred at 10° C. for16 hr to give a yellow solution. TLC (DCM/MeOH=10/1 Rf=0.6) showed a newspot was detected. H₂O (30 mL) was added and it was extracted with EtOAc(30 mL×2). The combined organic layer was dried over Na₂SO₄ andconcentrated in vacuo to give a yellow oil. The crude was purified bysilica gel chromatography (DCM/MeOH=10/1 to 3/1) to give the titlecompound (600 mg, 2.0522 mmol, 97.976% yield) as white solid.

LC-MS Method1 0.692 min, MS (m/z) 293.2 (M+H⁺).

(1R,5S,6r)-3-benzyl-6-(1-phenyl-1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexane

To a solution of(1R,5S,6r)-3-benzyl-N-phenyl-3-azabicyclo[3.1.0]hexane-6-carboxamide(330 mg, 1.13 mmol) in DCM (10 mL) was added Tf₂O (0.39 mL, 2.26 mmol).After stirred for 5 min, TMSN₃ (0.59 mL, 4.51 mmol) was added and thereaction was stirred for 16 hr to give a yellow solution. H₂O (30 mL)was added and it was extracted with EtOAc (30 mL×2). The combinedorganic layer was dried over Na₂SO₄ and concentrated in vacuum to givethe title compound (298 mg, 0.9389 mmol, 83.184% yield) as yellow solid.

LC-MS Method1 0.712 min, MS (m/z) 318.1 (M+H⁺).

(1R,5S,6r)-6-(1-phenyl-1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexane

To a solution of(1R,5S,6r)-3-benzyl-6-(1-phenyl-1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexane(500 mg, 1.58 mmol) in MeOH (15 mL) was added Pd/C (50.0 mg). It wasstirred at 10° C. for under H₂ atmosphere for 3 hr to give a yellowsolid. It was filtered through a pad of celite and the filtrate wasconcentrated in vacuum to give the title compound (400 mg, 1.76 mmol,111.72% yield) as white solid.

LC-MS Method1 0.538 min, MS (m/z) 228.0 (M+H⁺).

(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(1-phenyl-1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

A solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (50 mg, 0.3200mmol), N-ethyl-N-isopropylpropan-2-amine (0.17 mL, 0.9700 mmol) and HATU(74.61 mg, 0.3900 mmol) in DMF (2 mL) was stirred at 10° C. for 30 min.Then (1R,5S,6r)-6-(1-phenyl-1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexane(66.34 mg, 0.2900 mmol) was added and the reaction mixture was stirredfor 16 hr to give a yellow solution. H₂O (10 mL) was added and it wasextracted with EtOAc (10 mL×2). The combined organic layer was driedover Na₂SO₄ and concentrated in vacuum to give a yellow oil. The crudewas purified by silica gel chromatography (DCM/EA=3/1 to 1/2) to givethe title compound (21.25 mg, 0.0584 mmol, 3.5987% yield) as a whitesolid.

LC-MS Method1: 364.1 [M+H⁺] ¹H NMR (400 MHz, DMSO-d₆) δ 12.94 (br s,1H), 7.64-7.72 (m, 5H), 6.35 (s, 1H), 4.38 (br d, J=12.30 Hz, 1H),3.90-3.98 (m, 2H), 3.58 (br dd, J=4.27, 12.55 Hz, 1H), 2.91-2.97 (m,1H), 2.35 (br dd, J=3.76, 7.78 Hz, 1H), 1.79 (br s, 1H), 1.20 (d, J=6.78Hz, 6H) Example 136(1R,5S,6r)-N-(propan-2-yl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide(1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylicacid

To a solution of ethyl(1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylate(400 mg, 1.37 mmol) in THF (5 mL) and H₂O (1 mL, 1.37 mmol) was addedLiOH.H₂O (172.82 mg, 4.12 mmol). The mixture was stirred at 25° C. for 3h to give brown suspension. The reaction was poured into H₂O (20 mL) andacidified with 1 N HCl to pH=3 to 4 and extracted with EtOAc (100 mL×3).The combined organic layers was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give as the title compound (310mg, 1.1774 mmol, 85.76% yield) white solid.

(1R,5S,6r)-N-(propan-2-yl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a mixture of(1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (50 mg, 0.19 mmol) in DMF (1.5 mL) were added isopropyl amine(16.55 mg, 0.1900 mmol), HATU (86.6 mg, 0.2300 mmol) and DIPEA (0.06 mL,0.3800 mmol). The mixture was stirred at 100° C. for 16 h to give brownmixture. LCMS showed the starting material was consumed completely. Thereaction mixture was filtered and the filtrate was purified by prep-HPLC(FA). The afforded flows were combined, concentrated to remove most ofCH₃CN and lyophilized to afford the title compound (6.83 mg, 0.0205mmol, 10.819% yield) as white powder.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.45 (s, 1H), 4.09-4.19 (m, 2H),3.95 (br dd, J=11.1, 4.3 Hz, 1H), 3.69 (br dd, J=12.5, 4.3 Hz, 2H), 3.10(dt, J=13.9, 7.1 Hz, 1H), 3.03 (s, 3H), 2.23-2.31 (m, 1H), 2.09-2.17 (m,1H), 1.60 (br s, 1H), 1.40 (s, 9H), 1.33 (d, J=6.9 Hz, 6H)

Example 137(1R,5S,6r)-N-tert-butyl-N-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide(1R,5S,6r)-N-tert-butyl-N-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a mixture of(1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (100 mg, 0.3800 mmol) in DMF (2 mL) were added tert-butylmethylamine (22.45 mg, 0.3800 mmol), HATU (173.19 mg, 0.4600 mmol) andDIPEA (0.13 mL, 0.7600 mmol). The mixture was stirred at 30° C. for 16 hto give yellow suspension. LCMS showed the starting material wasconsumed completely. The suspension was filtered and the filter cake waswashed with EtOAc (3 mL). The filter cake was dried in vacuo to affordthe title compound (72.08 mg, 0.2368 mmol, 62.347% yield) as whitesolid.

¹H NMR (400 MHz, DMSO-d6) δ ppm 13.07 (s, 1H), 12.94 (s, 1H), 7.87 (d,J=7.5 Hz, 1H), 6.45-6.52 (m, 1H), 6.50 (d, J=1.6 Hz, 1H), 6.35 (d, J=1.9Hz, 1H), 4.29 (d, J=12.0 Hz, 1H), 3.86-3.97 (m, 1H), 3.72-3.84 (m, 2H),3.39-3.49 (m, 1H), 2.89-3.05 (m, 1H), 1.90-1.96 (m, 1H), 1.85 (dt,J=7.4, 3.6 Hz, 1H), 1.30 (t, J=3.1 Hz, 1H), 1.18-1.23 (m, 6H), 1.02 (dd,J=6.5, 4.6 Hz, 6H)

Example 138(1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide(1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a solution of(1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-azabicyclo[3.1.0]hexane-6-carboxamidehydrochloride (80 mg, 0.4100 mmol) in DMF (3.2 mL) were added5-isopropyl-1H-pyrazole-3-carboxylic acid (63.49 mg, 0.4100 mmol), HATU(203.43 mg, 0.5400 mmol) and Et₃N (0.2 mL, 1.24 mmol). The mixture wasstirred at 20° C. for 16 hr. TLC (PE/EA=0/1) showed a new spot (rf=0.5)and the reaction was completed. The mixture was diluted with H₂O (10 mL)and extracted with EA (10 mL×2). The combined organic layers were washedwith H₂O (5 mL) and NH₄Cl (5 mL), dried over Na₂SO₄ and concentrated invacuum to give crude oil. The crude oil was purified by prep-TLC(PE/EA=0/1) to give crude product. The crude product was purified byprep-HPLC (FA) to give the title compound (20.8 mg, 0.0630 mmol, 15.287%yield) as white powder.

LC-MS Method1: 341.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=6.44 (br s, 1H), 4.13 (br s, 1H), 4.04(d, J=12.8 Hz, 1H), 3.94 (dd, J=4.0, 11.3 Hz, 1H), 3.68 (dd, J=4.1, 12.8Hz, 1H), 3.01-2.92 (m, 1H), 2.84 (s, 3H), 2.03-1.87 (m, 1H), 1.28 (s,3H), 1.24 (d, J=6.9 Hz, 6H), 1.21-1.14 (m, 1H), 0.98-0.66 (m, 3H), 0.58(br s, 1H)

Example 139[(1R,5S,6r)-6-(2,2-dimethyl-2,3-dihydro-1H-indole-1-carbonyl)-3-azabicyclo[3.1.0]hexan-3-yl][5-(propan-2-yl)-1H-pyrazol-3-yl]methanone[(1R,5S,6r)-6-(2,2-dimethyl-2,3-dihydro-1H-indole-1-carbonyl)-3-azabicyclo[3.1.0]hexan-3-yl][5-(propan-2-yl)-1H-pyrazol-3-yl]methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid and EDCI(55.95 mg, 0.2900 mmol) in Pyridine (3 mL) was added(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(2,2-dimethyl-2,3,3a,7a-tetrahydro-1H-indol-1-yl)methanoneTFA salt (49.88 mg, 0.1900 mmol), and the reaction mixture was stirredat 20° C. under N₂ for 16 hours. LCMS showed the desired peak was found.The reaction was diluted with H₂O (30 mL) and extracted with EtOAc (20mL×3). The combined organic layers were separated, then dried overNa₂SO₄ and concentrated in vacuum to give brown oil. The brown oil waspurified by prep-HPLC (NH₃) and the afforded flows were combined,concentrated to remove most of CH₃CN and lyophilized to afford the titlecompound (36.39 mg, 0.0927 mmol, 47.647% yield) as white solid.

LC-MS Method1: 393.1 [M+H⁺].

¹H NMR (400 MHz, CHLOROFORM-d) δ=7.23-6.89 (m, 411), 6.50 (s, 1H), 4.34(br d, J=11.5 Hz, 1H), 4.29-4.20 (m, 1H), 4.05 (dd, J=4.3, 11.6 Hz, 1H),3.81 (dd, J=4.4, 12.9 Hz, 111), 3.13-2.87 (m, 3H), 2.54 (td, J=3.7, 7.3Hz, 1H), 2.32 (td, J=3.7, 7.2 Hz, 1H), 1.93 (br s, 1H), 1.61 (s, 3H),1.53 (br s, 3H), 1.30 (d, J=7.0 Hz, 6H)

Example 140(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[(4-methyl-2-thienyl)carbonyl]-3-azabicyclo[3.1.0]hex-3-yl}methanone(5-isopropyl-1H-pyrazol-3-yl){(1R,5S,6r)-6-[(4-methyl-2-thienyl)carbonyl]-3-azabicyclo[3.1.0]hex-3-yl}methanone

To a solution of(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(4-methyl-2-thienyl)methanone TFAsalt (60 mg, 0.2900 mmol) in DMF (2 mL) were added HATU (165.98 mg,0.4300 mmol) and Et₃N (0.07 mL, 0.5800 mmol), and the mixture wasstirred at 20° C. for 10 min under N₂. Then,5-isopropyl-1H-pyrazole-3-carboxylic acid (44.62 mg, 0.2900 mmol) in DMF(1 mL) was added, and the resulting mixture was stirred at 20° C. for 16hours to give a yellow mixture. The reaction mixture was poured into H₂O(5 mL) and extracted with EA (5 mL×3). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product was purified by Prep-HPLC(NH₃) and lyophilized to give the title compound (90 mg, 0.2621 mmol,90.535% yield) as a white solid.

LC-MS Method1: 344.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=10.33 (br s, 1H), 7.60 (d, J=0.8 Hz,1H), 7.26 (s, 1H), 6.53 (s, 1H), 4.37 (br d, J=11.5 Hz, 1H), 4.26 (d,J=13.1 Hz, 1H), 4.02 (dd, J=4.1, 11.7 Hz, 1H), 3.74 (dd, J=4.1, 12.9 Hz,1H), 3.04 (td, J=6.8, 13.7 Hz, 1H), 2.49 (td, J=3.5, 7.2 Hz, 1H), 2.38(td, J=3.6, 7.3 Hz, 1H), 2.34-2.31 (m, 1H), 2.30 (s, 3H), 1.32 (d, J=6.8Hz, 6H)

Example 141[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (38.5 mg,0.2500 mmol) in DMF (1.5 mL) were added HATU (112.84 mg, 0.3000 mmol),DIPEA (0.13 mL, 0.7900 mmol) and(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hexaneTFA salt (70 mg, 0.2300 mmol). The mixture was stirred at 20° C. for 12h to give brown solution. The mixture was poured into H₂O (15 mL) andextracted with EtOAc (15 mL×5). The combined organic layer was washedwith brine (50 mL), dried over Na₂SO₄ and concentrated to dryness. Theresidue was purified by prep-TLC (PE:EtOAc=1:1) to give white solid. Theresidue was purified by prep-HPLC (NH₃). The afforded flows werecombined, concentrated to remove most of CH₃CN and lyophilized to givethe title compound (3.63 mg, 0.0110 mmol, 4.8386% yield) as a whitesolid.

LC-MS Method1: 331.0 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.50 (1H, s), 4.09-4.18 (1H, m),4.01 (1H, br d, J=11.54 Hz), 3.81-3.95 (2H, m), 3.03 (1H, dt, J=13.93,7.09 Hz), 2.68 (2H, s), 2.22 (1H, dd, J=8.16, 5.40 Hz), 2.06 (1H, dd,J=7.91, 4.14 Hz), 1.38 (6H, d, J=2.26 Hz), 1.31 (6H, d, J=7.03 Hz), 1.17(3H, s)

Example 142[5-(1-cyclopropylethyl)-1H-pyrazol-3-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]methanone[5-(1-cyclopropylethyl)-1H-pyrazol-3-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a stirred solution of(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hexaneTFA salt (40 mg, 0.2200 mmol) and HATU (110.32 mg, 0.2900 mmol) in DMF(1 mL) was added DIPEA (0.23 mL, 1.33 mmol). After stirred for 30 min,5-(1-cyclopropylethyl)-1H-pyrazole-3-carboxylic acid (68.44 mg, 0.2200mmol) was added. The reaction mixture was stirred at 20° C. for 16 h togive a yellow solution. LCMS showed a new peak gives the desired ms. H₂O(30 mL) was added and it was extracted with EtOAc (30 mL×2). Thecombined organic layer dried over Na₂SO₄ and concentrated in vacuum togive a yellow oil. The crude was purified by prep-HPLC (NH₃). Theafforded flows were concentrated in vacuum to remove most of CH₃CN andlyophilized to give the title compound (16.69 mg, 0.0468 mmol, 21.093%yield) as white solid.

LC-MS Method1: 357.2 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ 6.58 (s, 1H), 4.11-4.17 (m, 1H),4.00-4.08 (m, 1H), 3.82-3.92 (m, 2H), 2.67 (s, 2H), 2.21 (dd, J=5.40,7.91 Hz, 1H), 2.13 (dd, J=7.03, 9.03 Hz, 1H), 2.04 (dd, J=5.02, 7.03 Hz,1H), 1.36-1.40 (m, 9H), 1.17 (d, J=0.75 Hz, 3H), 0.88-0.97 (m, 1H), 0.58(br d, J=7.28 Hz, 2H), 0.20-0.31 (m, 2H)

Example 143(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone

A 100 mL round-bottom flask was charged with5-isopropyl-1H-pyrazole-3-carboxylic acid (50.34 mg, 0.3300 mmol), HATU(149.78 mg, 0.3900 mmol), N-ethyl-N-isopropylpropan-2-amine (0.17 mL,0.9800 mmol) and DMF (1.6108 mL). After stirred for 30 min,6-[(1R,5S,6r)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-eneTFA salt (100 mg, 0.3300 mmol) was added. The reaction mixture wasstirred at 10° C. for 1 hr to give a yellow solution. The reactionmixture was diluted with H₂O (20 mL) and extracted with EtOAc (30 mL×2).The combined organic layer was dried over Na₂SO₄ and concentrated invacuum to give a residue as yellow oil. The crude was purified byPrep-HPLC (NH₃). The afford flows was concentrated in vacuum to removemost of CH₃CN and lyophilized to give the title compound (48.63 mg,0.1481 mmol, 45.353% yield) as white solid.

LC-MS Method1: 329.2 [M+H⁺] ¹H NMR (400 MHz, CHLOROFORM-d) δ=6.50 (s,1H), 4.19-4.10 (m, 1H), 4.03 (br d, J=11.9 Hz, 1H), 3.94-3.84 (m, 2H),3.06-2.98 (m, 3H), 2.26 (m, 1H), 2.16-2.07 (m, 1H), 1.30 (d, J=7.2 Hz,6H), 1.20 (s, 3H), 1.15-1.10 (m, 2H), 0.74-0.69 (m, 2H) Example 144(5-cyclopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone(5-cyclopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl-3-azabicyclo[3.1.0]hex-3-yl]methanone

To a solution of 5-cyclopropyl-1H-pyrazole-3-carboxylic acid (21.86 mg,0.1400 mmol) in Pyridine (1.5 mL) were added EDCI (62.59 mg, 0.3300mmol) and6-[(1R,5S,6r)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-eneTFA salt (40 mg, 0.1300 mmol). The mixture was stirred at 25° C. for 2 hto give a yellow solution. LCMS showed the desire MS as a major peak.The reaction mixture was concentrated directly. The residue was purifiedby prep-HPLC (NH₃) to give the title compound (11.2 mg, 0.0343 mmol,26.275% yield) as yellow solid.

LC-MS Method1: 327.1 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.35 (1H, s), 4.07-4.16 (1H, m),3.95-4.02 (1H, m), 3.83-3.95 (2H, m), 3.01 (2H, s), 2.27 (1H, dd,J=8.16, 5.40 Hz), 2.12 (1H, dd, J=7.40, 4.64 Hz), 1.88-1.95 (1H, m),1.18-1.22 (3H, m), 1.11-1.17 (2H, m), 0.95-1.02 (2H, m), 0.71-0.79 (4H,m)

Example 145(1R,5S,6r)-N-tert-butyl-6-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide(1R,5S,6r)-N-tert-butyl-6-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (15.71 mg,0.10 mmol) in DMF (0.50 mL) were added HATU (50.64 mg, 0.13 mmol) andEt₃N (0.04 mL, 0.31 mmol). The mixture was stirred at 20 to 25° C. for0.5 h. Then(1R,5S,6r)-6-methyl-N-(tert-butyl)-3-azabicyclo[3.1.0]hexane-6-carboxamideTFA salt (20 mg, 0.10 mmol) was added to the mixture. The resultingmixture was stirred at 20 to 25° C. for 2 h. LCMS showed the desired MS(as a major peak). The residue was purified by prep-HPLC (NH₃). Theafforded flows were combined, concentrated to remove most of CH₃CN andlyophilized to afford the title compound (6.94 mg, 0.0209 mmol, 20.489%yield) as a white solid.

LC-MS Method1: 333.3 [M+H⁺]

¹H NMR (400 MHz, CHLOROFORM-d) δ=6.49 (s, 1H), 5.59 (s, 1H), 4.13 (dd,J=5.7, 11.9 Hz, 1H), 3.95-3.86 (m, 2H), 3.79-3.71 (m, 1H), 3.03 (td,J=6.9, 13.8 Hz, 1H), 2.33 (dd, J=5.4, 8.1 Hz, 1H), 2.18 (dd, J=5.4, 8.0Hz, 1H), 1.36 (s, 9H), 1.31 (d, J=6.9 Hz, 6H), 1.14 (s, 3H)

Biological Example 1

Biochemical KDM5A inhibition assay

Using 384-well white Greiner784075 (Greiner), representative compoundswere characterized for their inhibition of KDM5A using HTRF® technology(Cisbio Bioassays). Briefly, the test compounds, reference compounds,and DMSO control (typical compound concentration range 1 pM-10 μM, finalassay concentration (FAC*) of DMSO 0.5%) were added to 384-well plate bythe Echo® acoustic dispensing platform (Labcyte). Five (5) μl of KDM5Aprotein (produced by the method described in Nat Chem Biol 12, 531-538(2016)). (5-20 nM FAC*) in assay buffer (50 mM MES, 50 mM NaCl, 1 mMTCEP, 0.01% v/v Tween 20, 0.03% BSA, pH 6.5) was added to wells andplates were incubated for 10-20 minutes at 25 degrees celsius. Then, 5μl of alpha-ketoglutaric acid (100 μM FAC*), biotin-labelled H3K4-Me3substrate (Anaspec Cat #AS-64357-1; 200 nM FAC*), Fe(II)SO₄ (100 μMFAC*) and ascorbic acid (2 mM FAC*) in assay buffer was added to wellsand plates were incubated for 20 minutes at room temperature. Thereaction was stopped with the addition of 10 μl of anti-H3K4-Me2-Eu(K)(Cisbio Bioassays Cat #61KA2KAH; 0.75 nM FAC**)+Streptavidin XL665(Cisbio Bioassays Cat #610SAXLB; 25 nM FAC**) in HTRF detection buffer(Cisbio Bioassays Cat #62SDBRDF). The mixture was incubated for 30minutes at room temperature before 340 nm excitation and measurement ofdual emission at 620 nm and 665 run.

*FAC: final assay concentration calculated based on 10 μl of the assaybuffer

**FAC: final assay concentration calculated based on 20 μl of thedetection buffer The raw data (a 665 nm and a 620 nm reading from eachwell) for individual assay plates were analyzed. The ratio of emissionswas calculated using the following calculation:

Ratio=(665 nm emission/620 nm emission)×10000.

Using DMSO control (maximum response or 0% inhibition) and 1 μMreference control compound (minimum response or 100% inhibition),percentage inhibition values for each well were calculated using themedian values of the minimum and maximum control wells and the followingcalculation:

% Inhibition=(Well ratio−max control ratio)/(min control ratio−maxcontrol ratio)×100.

Compound IC₅₀ values were calculated from graphs of % inhibition plottedagainst compound concentration, using a four parameter curve fit.

[Results]

The present compounds exhibited a strong KDM5 inhibitory activity. IC₅₀values (M) of representative present compounds are shown in the tablebelow. IC₅₀ values (μM) of comparative compound,(R)—N-(1-(3-isopropyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropanecarboxamide (the compound of Examples 29 described in PTL 1 (thepamphlet of International Publication No. WO2016057924)) was 0.02 M.

EXAMPLE IC₅₀ value EXAMPLE IC₅₀ value No. (μ M) No. (μ M) Example 1 0.02Example 82 0.03 Example 9 0.4 Example 84 0.03 Example 12 0.06 Example 850.02 Example 22 0.4 Example 87 0.04 Example 24 0.2 Example 88 0.07Example 27 1.0 Example 90 0.05 Example 33 0.03 Example 93 0.2 Example 400.2 Example 96 0.03 Example 51 0.02 Example 103 0.2 Example 55 0.02Example 104 0.04 Example 56 0.2 Example 106 0.04 Example 59 0.02 Example110 0.05 Example 60 0.2 Example 119 0.3 Example 62 0.01 Example 121 0.04Example 63 0.01 Example 124 0.04 Example 65 0.02 Example 131 0.01Example 66 0.03 Example 132 0.04 Example 69 0.2 Example 134 0.004Example 75 0.4 Example 136 0.05 Example 76 0.06 Example 138 0.8 Example77 0.02 Example 144 0.02 Example 81 0.06 Example 145 0.09

Biological Example 2 Metabolic Stability in Human Liver Microsomes

Human liver microsome (BD Gentest Corporation, Cat No. #452161)incubations were conducted in duplicate in 96-well plates. Each wellcontains 40 μL of 0.1 M potassium phosphate buffer (pH 7.4), 4.125 mMMgCl₂, 0.625 mg/mL liver microsomes, and test compound (1.25 μM). After5-min preincubation at 37° C., 10 uL of 5.0 mM NADPH in 0.1M potassiumphosphate buffer was added to initiate the enzymatic reaction. The finalcomponent concentrations are 0.1M potassium phosphate buffer (pH 7.4),1.0 mM NADPH, 3.3 mM MgCl₂, 0.5 mg/mL liver microsomes, and testcompound (1.0 μM). Reactions were terminated at 0 and 60 min by adding200 μL of ice-cold acetonitrile containing internal standard.

LC-MS/MS analysis was conducted as specified below.

LC System ACQUITY UPLC H-Class PLUS System (Waters) Column ACQUITY UPLCBEH C18 Column 2.1 mm ID × 50 mm (Waters) Elution Column temperature:25° C. conditions Mobile phase: A: water (0.1% formic acid) B:acetonitrile (0.1% formic acid) Gradient program: Time (min) 0 1.20 1.401.41 1.50 Mobile phase B (%) 10 90 90 10 10 Flow rate: 0.6 mL/min MSSystem API4000 (AB Sciex) Condition Electrospray ionization, positiveion mode, multiple reaction monitoring mode

The remaining at 60 min (%) of test compound was calculated from thepeak area ratio (test compound/internal standard) of samples collected 0and 60 min after the start of the reaction according to the formuladescribed below.

Remaining at 60 min (%)=peak area ratio of sample collected at 60min/peak area ratio of sample collected at 0 min×100

[Results]

The present compounds were stable against hepatic metabolism. Themetabolic stability in human liver microsomes of representative presentcompounds are shown in the table below.

Metabolic stability in human liver microsomes (% remaining EXAMPLE No.at 60 min) Example 1 95 Example 9 93 Examplel2 100 Example 24 101Example 27 97 Example 33 103 Example 40 103 Example 51 95 Example 59 100Example 60 102 Example 62 83 Example 65 93 Example 66 89 Example 69 89Example 75 102 Example 81 100 Example 82 104 Example 84 92 Example 85 98Example 87 99 Example 88 95 Example 90 100 Example 93 86 Example 96 83Example 110 85 Example 119 102 Example 121 114 Example 124 97 Example131 84 Example 136 97 Example 144 101 Example 145 99

Biological Example 3 Brain Concentration in Mice

Test compounds were orally administered to mice (C57BL/6) at 1 or 3mg/kg. Brain samples were collected 2 h after the administration andhomogenized with 3-fold volumes of distilled water.

LC-MS/MS analysis was conducted as specified below. Standard calibrationsamples were prepared using the same matrix and analyzed in the samemanner.

Extraction Mix 40 μL of sample with 40 μL of acetonitrile procedure and160 μL of acetonitrile/ethanol (7:3) containing internal standard, andstir the mixture. Transfer all to a deproteinization filter plate forsuction filtration and inject the filtrate to a LC system. LC SystemProminence UFLC_(XR) (Shimadzu Corporation) Column Shim-pack XR-ODSII2.0 mm ID × 75 mm (Shimadzu Corporation) Elution Column temperature: 40°C. conditions Mobile phase: A: 0.2% formic acid 5 mM ammonium acetateaqueous solution B: acetonitrile Gradient program: Time (min) 0 1.5 3.03.1 4 Mobile phase B (%) 10 90 90 10 10 Flow rate: 0.5 mL/min MS SystemAPI4000 (AB Sciex) Condition Electrospray ionization, positive ion mode,multiple reaction monitoring mode

Standard calibration samples were analyzed to calculate a regressionequation from the peak area ratio (test compound/internal standard). Thepeak area ratio was determined for a measurement sample and assigned tothe regression equation to calculate an assay value.

[Results]

The Unbound-Brain Concentration of the present compounds was high. TheUnbound-Brain Concentration at 2 h at 1 mg/kg of representative presentcompounds are shown in the table below. Values with * are obtained byproportional calculation from the 3 mg/kg data. Unbound-BrainConcentration at 2 h of comparative compound,(R)—N-(1-(3-isopropyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropanecarboxamide (the compound of Examples 29 described in PTL 1 (thepamphlet of International Publication No. WO2016057924)) was 2.5 ng/g.

Unbound-Brain Concentration at 2 h EXAMPLE No. at 1 mg/kg (ng/g) Example1 93.7* Example 12 10.8 Example 33 62.1 Example 51 55.3 Example 81 21.9Example 82 57.4 Example 85 76.7 Example 88 39.5*

Formulation Example 1

Tablets containing 5 mg of[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

The following components can be mixed and compressed to tabletsaccording to standard methods to obtain 10,000 tablets each containing 5mg of the active component.

-   -   [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone:        50 g    -   Carboxymethylcellulose calcium (disintegrating agent): 20 g    -   Magnesium stearate (lubricant): 10 g    -   Microcrystalline cellulose: 920 g

Formulation Example 2

Tablets containing 5 mg of[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone

The following components can be mixed and compressed to tabletsaccording to standard methods to obtain 10,000 tablets each containing 5mg of the active component.

-   -   [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone:50        g    -   Carboxymethylcellulose calcium (disintegrating agent): 20 g    -   Magnesium stearate (lubricant): 10 g    -   Microcrystalline cellulose: 920 g

Formulation Example 3

Injections containing 20 mg of[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone

The following components can be mixed according to the standard method,and the solution can be then sterilised according to the standardmethod, divided into ampoules at 5-mL aliquot and lyophilised accordingto the standard method to obtain 10,000 ampoules each containing 20 mgof the active component.

-   -   [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone:        200 g    -   Mannitol: 20 g    -   Distilled water: 50 L

INDUSTRIAL APPLICABILITY

The present compound has KDM5 inhibitory activity, and thus is useful asa prophylactic and/or therapeutic agent for cancer, Huntington'sdisease, Alzheimer's disease and the like.

1.[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone,or a salt thereof.
 2. A compound of the formula:


3. A salt of a compound of the formula: